bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–09–27
eighty-one papers selected by
Cédric Chaveroux, CNRS
  1. Beyond Translation Initiation: Translational Elongation, Decoding Fidelity, and Ribosome Surveillance During Branched-Chain Amino Acid Deprivation, with a Focus on Mammalian Systems.
  2. Stress granules and RNA-binding proteins in cellular senescence: a modular perspective on stress adaptation and inflammation.
  3. The p53-Associated Regulation of ATF4 mRNA Expression Involves p21 and p130 in a Stress-Dependent Manner.
  4. RpS19a depletion alters the hematopoietic translatome to drive tissue overgrowth.
  5. Determinants of C16-Ceramide Binding to p53.
  6. Role of the m6A methyltransferase Mettl16 in Drosophila development.
  7. The stability of m6A-marked transcripts is linked to cell identity in planarians.
  8. Halting translation by the letter with sequence-selective small molecules.
  9. Gestational stage alters insulin and mTOR signaling in bovine maternal placentome and fetal liver.
  10. RNA-Binding Peptide Influences Epitranscriptomic Regulation by Preferentially Binding to Unmodified RNAs Targeted by NSUN2.
  11. Investigating the role of phosphodiesterase Pde2 in coordinating resource reallocation through the environmental stress response.
  12. Engineered mRNA nanostructures expand the design space of mRNA therapeutics through programmable protein expression and immune stimulation.
  13. Local translation couples synaptic activity to mitochondrial adaptation in dendrites.
  14. Enterovirus RNase L inhibiting RNAs are highly conserved with limited phylogenetic distribution.
  15. Vitamin B6 Modifies Tau-Induced Cellular Stress- and Proteostasis-Related Responses.
  16. RNA derived from cancer cells as a scaffold for amyloid-β25-35 aggregation: the effect of RNA methylation and rRNA status.
  17. Emerging Roles of tRNA Modifications in Translational Adaptation of Human Fungal Pathogens.
  18. Transcriptomic Reprogramming of the Human Placenta Following Maternal Opioid Exposure: Identification of Altered Metabolic and Translational Pathways.
  19. Single-cell visual proteomics of a minimal bacterium reveals structural coordination of gene expression machineries.
  20. Ribotoxic Stress, ZAK Activation and the Orchestration of Inflammatory Signaling Networks in Human Disease.
  21. Influence of Endoplasmic Reticulum Stress on Urokinase Plasminogen Activation.
  22. Activity-based profiling of bacterial RNA-modifying enzymes reveals species-specific 5-methyluridine modification in Bacillus subtilis 23S rRNA.
  23. Long-term imoxin treatment does not attenuate disease severity in dystrophic diaphragm of male mice.
  24. Aminoacyl-tRNA synthetases in tumor immunity: canonical translation, source-resolved immune circuits and therapeutic opportunities.
  25. Reassessment of IRES Element Activity in Komagataella phaffii Using a Standardized Bicistronic System: Cryptic Promoter Activity Mimics Cap-Independent Translation.
  26. Mitochondrial Quality Control Imbalance in the Heterogeneity of Parkinson's Disease: From Selective Vulnerability to Stratified Transformation.
  27. Beyond m6A: The Expanding Landscape of mRNA Modifications in Renal Cell Carcinoma.
  28. A human cell-free translation screen identifies the NT-2 mycotoxin as a ribosomal inhibitor that binds the peptidyl transferase center.
  29. Targeting the METTL5-MGST1 axis for cancer therapy: molecular mechanisms and therapeutic implications.
  30. Diaphragmatic Mitochondrial Myopathy in a Patient-Derived Mouse Model of Barth Syndrome.
  31. Alternative RNA Splicing in Cancer: Molecular Mechanisms, Functional Consequences, Biomarkers and Therapeutic Opportunities.
  32. [NPLOC4 promotes proliferation, invasion, and migration of hepatocellular carcinoma cells via enhancing Wnt/β-catenin-mediated mitophagy].
  33. TOR-NOT4 signalling couples translation to co-translational quality control in plants.
  34. Dual promoter architecture of NFE2L2 underlies isoform-specific translational control of NRF2.
  35. TANGO6 coordinates transcription and translation through nucleocytoplasmic partitioning.
  36. Kinase crosstalk coordinates stress adaptation and metabolic homeostasis in plants.
  37. Epitranscriptomic Regulation in Oncogenic Viruses: Emerging Roles of RNA Modifications in Viral Persistence and Tumourigenesis.
  38. Clerodendrum japonicum Extract Suppresses the Pathogenicity of Rheumatoid Arthritis Fibroblast-Like Synoviocytes by Inhibiting METTL3-Mediated ICAM2 mRNA Methylation.
  39. Viral Strategies and Cellular Countermeasures That Regulate mRNA Access to the Translation Apparatus: Second Edition.
  40. Proteomic Profiling Reveals Intracellular Regulatory Network Disturbance Induced by QseB Deletion in Glaesserella parasuis.
  41. Natural Small Molecules Targeting Mitochondrial Quality Control for the Treatment of Metabolic Diseases: Mechanisms, Novel Formulations, and Translational Perspectives.
  42. YTHDF3 promotes angiogenesis in endometriosis by enhancing the translation efficiency of PFKFB3.
  43. URMylation Signaling Pathway in Cancer: Molecular Mechanisms and Therapeutic Opportunities.
  44. Translational dysregulation as a mechanistic driver of cognitive, behavioral, and affective phenotypes in FXS and TSC.
  45. USP19 protects against cigarette smoke-induced lung injury and epithelial stress.
  46. Lost in translation – moralsk stress eller moralsk belastning?
  47. METTL3-Mediated N6-Methyladenosine Modification Activates the EGR1-ZBP1 Axis to Promote PANoptosis-Like Cardiomyocyte Death in Myocardial Ischemia-Reperfusion Injury.
  48. Structural basis of step II spliced leader RNA trans-splicing in trypanosomatid parasites.
  49. The Histone Demethylase JMJD2-Dependent Regulation of rDNA Transcription and Integrity of Nucleolus Is Required for Fungal Development and Pathogenicity in the Rice Blast Fungus.
  50. The splicing axis of aging: mechanisms and therapeutic opportunities.
  51. IGF2BP3 remodels RISC occupancy to control microRNA targeting in leukemia.
  52. A Pilot Proteomics Analysis of Mycobacterium tuberculosis Lacking a Putative Short-Chain Dehydrogenase Rv0148.
  53. The rapid emergence of small molecule RNA modulator hit discovery: unlocking the potential.
  54. METTL16 promotes colorectal cancer progression and CD8+ T cell function through BCAT1-dependent branched-chain amino acid metabolism.
  55. Acteoside alleviates Parkinson's disease-associated neurodegeneration and oxidative stress via an m6A-dependent Nrf2 regulatory axis.
  56. A jumbo cyanophage encodes the most complete ribosomal protein set in the known virosphere.
  57. A Novel Translational Reprogramming of the Insertion Sequence IS1239 by 1-bp Deletion Resulted in Polymorphism of C-Terminal Amino Acid Sequences in the Pathogenic Bacterium Streptococcus pyogenes.
  58. Stress-dependent ribosome-associated proteomics reveals a role for Sis1 in thermotolerance and virulence in Cryptococcus neoformans.
  59. Mechanistic Insight into the Role of Maresin-1 in Attenuating Lithium-Induced Nephrogenic Diabetes Insipidus in Rats via Regulation of cAMP/AQP2 Signaling and SERCA2b Dependant Endoplasmic Reticulum Stress.
  60. Extracellular vesicles shape tumourigenesis: from signalling networks to systemic progression.
  61. Itaconation and Succination as Metabolite-Derived Cysteine Modifications in Inflammatory Signalling: Biochemical Mechanisms, Chemoproteomic Mapping, and Therapeutic Opportunities.
  62. Advances in RNA m6A modification research and its role in poultry economic traits.
  63. Coordinated regulation of the metaboproteome by Hsp90 chaperones controls metabolic plasticity.
  64. HMGB1 Post-Translational Modifications in Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma: Current Evidence, Emerging Mechanistic Concepts, and Unresolved Questions.
  65. Turnera diffusa polysaccharides promote healthy aging through conserved stress response regulation and metabolic remodeling across multiple aging models.
  66. Aging-modulatory effects of Pausinystalia macroceras (K. Schum.) Pierre polysaccharides are associated with DAF-16/FOXO and SKN-1/Nrf2 signaling in multiple aging models.
  67. Nucleolar reorganization on stress depends on physicochemical changes due to reduced nascent rRNA synthesis.
  68. Alternative splicing-dependent T218 phosphoregulation controls SR45.1 nuclear organization and salt stress responses in Arabidopsis.
  69. Alterations of Gene Expression and Signaling Pathway Activity in Venous Smooth Muscle Cells After Uremic Serum Exposure.
  70. Mitochondrial Modulation as a Therapeutic Entry Point in Neurodegeneration.
  71. mTOR signaling in aging: from causality to geroprotective interventions and hallmark-level outcomes.
  72. Atherosclerotic Cell Fates: A Single-Cell View of ER Stress.
  73. METTL3/IGF2BP1 Axis Orchestrates m6A-Dependent NCAM1 Preservation to Combat Age-Related Cognitive Decline.
  74. Comparative Analysis of Reported Gene Targets and Binding Regions of Glu-CTC tRNA Fragments Across Human Diseases.
  75. Specific host translation perturbations promote Tn Smu 1 loss independently of the canonical ImmA regulator.
  76. Biosynthesis and Synthesis of Griseoviridin and Viridogrisein.
  77. Stress granule phase transitions and neuronal fate in cerebral ischemia-reperfusion injury.
  78. METTL3 promotes human coronavirus replication through an interferon-independent mechanism.
  79. AUG-Dependent Translation of Antisense Repeat Transcripts Contributes to Dipeptide Repeat Protein Production in C9ORF72 Expansion Carriers.
  80. Heat shock protein genes Hsp70 and DnaJA1 are key contributors to thermotolerance and development in predatory ladybeetle Propylaea japonica.
  81. Molecular Details of RNA Interactions With FUS Condensates Altering Assembly, Dynamics, and Aggregation.
  1. Biology (Basel). 2026 Sep 16. pii: 1629. [Epub ahead of print]15(18):
    Beyond Translation Initiation: Translational Elongation, Decoding Fidelity, and Ribosome Surveillance During Branched-Chain Amino Acid Deprivation, with a Focus on Mammalian Systems.
    Mutsuki Ojima, Manami Matsuura, Miwako Deguchi, Dong-Ho Kim.
      In mammalian systems, translational responses to amino acid limitation are commonly framed as mechanistic target of rapamycin complex 1 (mTORC1) inhibition and activation of the general control nonderepressible 2 (GCN2)-eukaryotic initiation factor 2α (eIF2α) arm of the integrated stress response. Suppressing initiation, however, does not immediately relieve aminoacylated transfer RNA shortages for ribosomes already engaged on messenger RNA. Transfer RNA charging and ribosome profiling reveal codon- and isoacceptor-specific elongation constraints. Across mouse NIH3T3 and several human cell systems, leucine deprivation often appears initiation-dominant but can produce UUA-biased pausing and frameshifting in selected cancer cells. Valine deprivation can prolong decoding at all four valine codons, whereas separate isoleucine-deprivation studies report AUU/AUC-selective slowing, a cytoplasmic isoleucyl-tRNA synthetase 1 (IARS1)-linked isoleucine-to-valine signal in exogenous reporter peptides, and an isoleucine-to-methionine substitution signal of unresolved mechanism. Ribosome slowing can engage global, transcript-local, and quality-control feedback, but the inputs are stress- and system-dependent. We propose a two-layer kinetic framework separating (i) A-site competition among correct decoding, substitution, and abortive exit from (ii) collision formation set by ribosome influx and dwell time. It keeps protein quantity, sequence fidelity, retained function, and proteostasis cost separate, and defines a matched measurement roadmap from metabolite flux to protein function.
    Keywords:  GCN2; aminoacyl-tRNA; branched-chain amino acids; integrated stress response; mistranslation; ribosome collision; ribosome stalling; ribosome-associated quality control
    DOI:  https://doi.org/10.3390/biology15181629
  2. Mol Biol Rep. 2026 Sep 25. pii: 1622. [Epub ahead of print]53(1):
    Stress granules and RNA-binding proteins in cellular senescence: a modular perspective on stress adaptation and inflammation.
    Maryam Bahraminasab, Janan Saleh Al-Rashdi, Mahmoud Darweesh, Saeed Mohammadi, Issa Sulaiman Al-Amri, Ahmed Al-Harrasi, Maha Rashid Al-Roshdi.
      Cellular senescence is a complex stress response characterized not only by stable growth arrest but also by chromatin remodeling, altered proteostasis, metabolic adaptation, innate immune activation, and the senescence-associated secretory phenotype. Stress granules (SGs) are dynamic membraneless ribonucleoprotein condensates that form during translational stress and regulate mRNA triage, signaling and recovery. While both senescence and SGs represent important features of cellular stress response, the mechanisms underlying their intersection remain poorly defined. This review examines how the biology of SGs and RNA-binding proteins (RBPs) regulate senescence, with particular emphasis on stress granule-induced inflammation associated with SASP, activation of cGAS-STING, induction of NF- κB signaling, and interferon response. We discuss the differential ability of senescence inducers to generate canonical SGs and why SG formation does not necessarily result in global translational shutdown. In addition, we examine the potential roles of SG-associated RBPs, including G3BP1/2, TIA1/TIAR, CAPRIN1, USP10, HuR, ZFP36 family, FXR1, and TDP-43 together with methodological standards for identifying SGs in senescence. We present a stage-resolved modular framework describing the context-dependent functions of SG-associated RBPs throughout senescence progression and discuss therapeutic opportunities. Overall, this review suggests that stress granules and associated RNA-binding proteins should be considered context-dependent components in inflammation-driven senescence, rather than universal inducers of senescence onset.
    Keywords:  Biomolecular condensates; Cellular senescence; Inflammatory remodeling; Integrated stress response; RNA binding proteins; Stress granules
    DOI:  https://doi.org/10.1007/s11033-026-12735-5
  3. Cells. 2026 Sep 20. pii: 1713. [Epub ahead of print]15(18):
    The p53-Associated Regulation of ATF4 mRNA Expression Involves p21 and p130 in a Stress-Dependent Manner.
    Alexandra Dalina, Maria Shilyaeva, Irina Kovaleva, Peter Chumakov.
      p53-dependent signaling and the integrated stress response (ISR) are major stress response programs that coordinate cellular metabolism and cell fate decisions. While p53 activation often promotes cell cycle arrest and cell death, the ISR can support either adaptive survival or cell death depending on the cellular context. Although increasing evidence indicates the crosstalk between these pathways, the underlying mechanisms remain incompletely understood. Here, we show that p53 activation is associated with reduced ATF4 mRNA expression under basal conditions and during selected metabolic stresses, including mitochondrial dysfunction. Knockdown experiments have demonstrated that p21 and p130 contribute to this response in a stress-dependent manner. Our findings identify a context-dependent link between p53 signaling and ATF4 mRNA regulation and suggest that p53, p21, and p130 may influence the ATF4-dependent branch of the ISR during cellular stress.
    Keywords:  ATF4; cancer; electron transport chain inhibition; hypoxia; integrated stress response; nutrient deprivation; p130; p21; p53
    DOI:  https://doi.org/10.3390/cells15181713
  4. iScience. 2026 Oct 16. 29(10): 117515
    RpS19a depletion alters the hematopoietic translatome to drive tissue overgrowth.
    Naomi C Mitchell, Arjun Chahal, Tanya Javaid, Katrina Woodward, Ralf B Schittenhelm, Cheng Huang, Julie Lorent, Jiwon Lee, Melanie Rug, Amee J George, Ross D Hannan, Ola Larsson, Anthony W Purcell, Eduardo Eyras, Nikolay Shirokikh, Teresa T Bonello, Leonie M Quinn, Olga Zaytseva.
      Despite ribosomal protein loss correlating with increased tumor predisposition, direct mechanisms for the counterintuitive oncogenic effect of ribosomal protein depletion have not been reported. We used genetic models to investigate ribosomal protein S19a (RpS19a) depletion in the Drosophila blood organ, the lymph gland. Intriguingly, we demonstrate that RpS19a depletion directly drives excess proliferation and tissue overgrowth. Proteomic and differential translation analysis of RpS19a-depleted cells revealed altered stoichiometry of translation initiation factors and increased association of ribosomes with mRNAs encoding growth-promoting proteins. Furthermore, ribosomes in RpS19a-depleted cells are associated with mRNA encoding dNep1, a putative ribosomal RNA methyltransferase. Although uncharacterized in Drosophila, NEP1 is implicated in ribosomal RNA methylation and ribosome stability in yeast and humans, and its mutations underpin the ribosomopathy Bowen-Conradi syndrome. The RpS19a knockdown phenotype is suppressed by dNep1 co-depletion, altogether suggesting that dNep1 enables assembly of pro-proliferative ribosomes essential for blood lineage overgrowth driven by ribosomal protein loss.
    Keywords:  Drosophila; NEP1; RpS19a; blood; growth control; lymph gland; protein translation; ribosomal protein; ribosomopathy
    DOI:  https://doi.org/10.1016/j.isci.2026.117515
  5. Biomolecules. 2026 Sep 15. pii: 1343. [Epub ahead of print]16(9):
    Determinants of C16-Ceramide Binding to p53.
    Madeline S Childress, Kristen A Jeffries, Sergey A Krupenko, Natalia I Krupenko.
      The tumor suppressor p53 coordinates cellular stress responses, but underlying mechanisms remain incompletely understood. We previously demonstrated that, in response to metabolic stress, C16-ceramide produced by ceramide synthase 6 (CerS6) directly binds to p53, thus preventing its MDM2-mediated degradation and promoting p53 activation. Here, we investigated the structural requirements and functional consequences of ceramide binding to p53. Using a panel of p53 mutants, including naturally occurring oncogenic variants, we characterized the ceramide-binding interface of p53 and the role of amino acid substitutions within this region in metabolic stress signaling. We found that disruption of ceramide binding impaired stress-induced p53-CerS6 interaction at the endoplasmic reticulum (ER), attenuated induction of p53 target genes, and reduced cellular sensitivity to stress. Of note, certain cancer-associated p53 mutants retained ceramide binding and the ability to activate stress responses. These studies were further extended to monitoring the p53-CerS6 interaction on the ER and associated membrane aggregation using fluorescence techniques. We showed that metabolic stress-induced ER remodeling was distinct from the canonical UPR. Overall, our study defines the ceramide-binding surface within the p53 DNA-binding domain and provides novel insight into the functional role of the ceramide-p53 interaction.
    Keywords:  C16-ceramide; CerS6; ER stress; mutant p53; p53 activation; sphingolipid signaling
    DOI:  https://doi.org/10.3390/biom16091343
  6. PLoS Genet. 2026 Sep;22(9): e1012317
    Role of the m6A methyltransferase Mettl16 in Drosophila development.
    Penghui Song, Lijuan Ma, Dong Yan.
      N6-methyladenosine (m6A), one of the most abundant chemical modifications on RNA, is installed by METTL3 and several other methyltransferases, including METTL16. Although METTL16 has been characterized in several model organisms, its function in Drosophila remains unknown. Here, we show that, unlike in mammals, Drosophila Mettl16 mutants are viable but exhibit multiple developmental and behavioral defects. Both male and female mutants are sterile, with severe gametogenesis defects. Mettl16 mutant germ cells can pass the mitotic and meiotic stages, but are defective in spermatid elongation and individualization. Mettl16-GFP localizes predominantly to the nucleus, and its absence does not impair global protein synthesis in wing disc epithelial cells. MeRIP-Seq analysis indicates that Mettl16 loss affects m6A on only a small subset of transcripts, in contrast to the broad effect of Mettl3. We further demonstrate that Mettl16 interacts with U6 snRNA and is required for its m6A modification. Accordingly, Mettl16 mutants display widespread alterations in alternative splicing. Together, the pleiotropic phenotypes of Mettl16 mutants likely stem from its role in m6A deposition and U6-dependent splicing regulation of specific target transcripts.
    DOI:  https://doi.org/10.1371/journal.pgen.1012317
  7. Nucleic Acids Res. 2026 Sep 22. pii: gkag892. [Epub ahead of print]54(18):
    The stability of m6A-marked transcripts is linked to cell identity in planarians.
    Constantin Höhn, Andreas Pittroff, Anne-Sophie Gribling-Burrer, Lisa Hülsmann, Redmond P Smyth, Claus-D Kuhn.
      N 6-methyladenosine (m6A) is a prevalent internal modification of eukaryotic mRNA that influences transcript fate, including mRNA stability and cell-type-specific gene expression. However, the mechanisms underlying m6A-mediated regulation remain poorly understood in many systems, including the highly regenerative planarian Schmidtea mediterranea. To address this, we generated a high-confidence atlas of ∼72 200 m6A sites across the planarian transcriptome using multiplexed direct RNA sequencing. The m6A sites follow a DRAYW consensus motif and are highly enriched near stop codons while being largely excluded from coding sequences. This pattern aligns with an exon and intron length-dependent variant of the exon junction complex (EJC)-mediated exclusion model, wherein the EJC restricts m6A deposition near splice sites. Knockdown of the m6A writer complex induced pronounced, cell-type-specific changes in transcript stability. Destabilized transcripts were enriched for intestinal markers, whereas stabilized transcripts were associated with neoblasts, the adult stem cells of planarians. Transcriptional shut-off experiments confirmed that m6A has opposing effects on mRNA decay depending on cellular context: it stabilizes transcripts in differentiated cells, while it promotes the degradation of mRNAs associated with neoblasts. Collectively, these results support a model in which cell-type-specific regulation of mRNA stability by m6A plays a crucial role in shaping cell identity in planarians.
    DOI:  https://doi.org/10.1093/nar/gkag892
  8. Nat Chem Biol. 2026 Sep 25.
    Halting translation by the letter with sequence-selective small molecules.
    Tilman Schneider-Poetsch, Minoru Yoshida, Takuhiro Ito, Shintaro Iwasaki.
      Protein synthesis forms the very basis of life. Cells rely on a sophisticated machinery of factors for the translation of an RNA template into a correct amino acid sequence. We owe a lot of our understanding of this process to specific small-molecule modulators. Since the discovery of antibiotics inhibiting bacterial protein synthesis, small molecules have served as probes to dissect the translation apparatus and as medications to fight disease. Advances in sequencing-based techniques and structural methods now provide for a highly detailed mechanistic understanding. Recent evidence shows that many translation modulators act in an RNA- or a peptide-sequence-selective manner. These molecules present exciting opportunities to better understand the translation machinery and provide new venues to modulate the expression of certain protein subpopulations. In this Review, we summarize recent findings on sequence-selective translation modulators, with emphasis on eukaryotes, the techniques that enabled their discovery, and offer an outlook into their potential applications.
    DOI:  https://doi.org/10.1038/s41589-026-02318-7
  9. Anim Reprod Sci. 2026 Sep 19. pii: S0378-4320(26)00218-6. [Epub ahead of print]294 108315
    Gestational stage alters insulin and mTOR signaling in bovine maternal placentome and fetal liver.
    Ahmad A Aboragah, Nithat Wichasit, Danielle N Sherlock, Fabiana D Cardoso, Felipe C Cardoso, Juan J Loor.
      Understanding stage-specific regulation of placental and fetal metabolic signaling pathways is essential to elucidate mechanisms supporting fetal growth and developmental programming in dairy cattle. This study evaluated differences in protein abundance between mid-gestation and late-gestation in placentome and fetal liver in lactating Holstein cows. In placentome tissue, late-gestation was characterized by a marked decrease in phosphorylated ribosomal protein S6 (p-RPS6; P = 0.01), suggesting reduced signaling through the mTOR-RPS6 axis, which is involved in the regulation of protein synthesis. In contrast, proteins associated with cellular stress response and detoxification were significantly elevated, including heat shock protein 70 (HSP70; P = 0.01) and glutathione S-transferase Mu 1 (GSTM1; P = 0.03), suggesting enhanced oxidative stress defense and protein-folding capacity as gestation advances. In fetal liver, late-gestation exhibited a pronounced reduction in insulin signaling, evidenced by lower AKT abundance (P = 0.01). Additionally, the ratio of phosphorylated to total mTOR (P = 0.03) and p-RPS6 abundance (P = 0.01) were decreased, further supporting attenuation of anabolic signaling pathways. Conversely, total eukaryotic elongation factor 2 (eEF2) abundance increased (P = 0.01), potentially reflecting a compensatory mechanism to sustain translational capacity despite reduced upstream signaling. Collectively, these data indicate a shift from anabolic growth signaling toward enhanced stress adaptation and selective translational control in late-gestation. The coordinated downregulation of insulin/mTOR signaling alongside increased stress-response proteins highlights tissue-specific adaptations that may optimize fetal development under changing metabolic demands.
    Keywords:  Lactation; Nutrigenomics; One-carbon metabolism; Oxidative stress; Pregnancy
    DOI:  https://doi.org/10.1016/j.anireprosci.2026.108315
  10. Biomolecules. 2026 Sep 05. pii: 1287. [Epub ahead of print]16(9):
    RNA-Binding Peptide Influences Epitranscriptomic Regulation by Preferentially Binding to Unmodified RNAs Targeted by NSUN2.
    Chathurani Ekanayake, Aftab Mollah, Maelee Thompson, Elizabeth Hout, Chamali Thalagaha Mudiyanselage, Sanjaya Abeysirigunawardena.
      5-Methylcytosine (m5C) is a widespread mRNA modification that regulates gene expression and is frequently dysregulated in cancer. Here, we used phage display to identify peptides that bind an NSUN2 consensus RNA sequence in either its unmodified (UN2-RNA) or m5C-modified (MN2-RNA) form. A single peptide, un2p1 (TDYSTHRLSHSL), was selectively enriched against both targets. Biophysical analyses demonstrated that un2p1 binds this RNA sequence with high affinity and that m5C incorporation reduces binding by approximately ninefold, indicating that cytidine methylation acts as a biochemical switch for peptide-RNA recognition. Sequence alignments mapped un2p1 to a conserved structural loop and catalytic domain region within NSUN2, suggesting that the peptide functions as a molecular mimic of the endogenous RNA-recognition interface. In A549 lung adenocarcinoma cells, un2p1 treatment reduced global m5C levels and downregulated the oncogenic chaperonin CCT5, consistent with disruption of NSUN2-dependent Wnt/β-catenin signaling. These effects were attenuated in non-malignant HEK293 cells, which exhibited a compensatory increase in m5C levels and preserved viability. Together, these findings identify un2p1 as a sequence-specific, methylation-sensitive RNA-binding peptide that modulates the m5C epitranscriptome and selectively impairs lung cancer cell viability, highlighting a substrate-centric strategy for targeting NSUN2-mediated oncogenic pathways.
    Keywords:  5-methylcytosine (m5C); NSUN2; RNA modifications; RNA-binding peptides; epitranscriptomics; phage display
    DOI:  https://doi.org/10.3390/biom16091287
  11. G3 (Bethesda). 2026 Sep 22. pii: jkag200. [Epub ahead of print]
    Investigating the role of phosphodiesterase Pde2 in coordinating resource reallocation through the environmental stress response.
    Rachel A Kocik, Jamie Ahrens, Audrey P Gasch.
      Yeast responding to acute stress reallocates cellular resources, in part via the environmental stress response (ESR) that induces stress-defense genes while repressing ribosome biogenesis and growth genes. The purpose and regulation of coordinated induction and repression are incompletely understood, but both responses are influenced by ESR transcription factors Msn2 and Msn4 (Msn2/4). Here, we used single-cell microscopy and transcriptomic analysis to investigate the role of the upstream regulator Pde2 in ESR regulation and poststress fitness. Loss of PDE2 weakened and shortened Msn2 activation following salt stress and produced muted induction of Msn2/4 targets, similar to a msn2Δmsn4Δ strain. In contrast, Pde2 had at most a minor impact on the ESR repressor Dot6, yet was important for repression of its targets beyond Msn2/4 influence. Consistent with our recent resource-reallocation model, pde2Δ cells had normal or faster poststress growth rates, despite weaker activation of the ESR. We discuss implications for ESR regulation and function.
    Keywords:  Pde2; environmental stress; fungi; regulatory dynamics; resource allocation
    DOI:  https://doi.org/10.1093/g3journal/jkag200
  12. bioRxiv. 2026 Sep 17. pii: 2026.09.14.751315. [Epub ahead of print]
    Engineered mRNA nanostructures expand the design space of mRNA therapeutics through programmable protein expression and immune stimulation.
    Mark D Knappenberger, Skylar J W Henry, Archana Kikla, Matthew Sample, Olivia Roy, Erik Poppleton, Nicholas Stephanopoulos, Michael P Gustafson, Karen S Anderson, Petr Šulc.
      Messenger RNA (mRNA) therapeutics have transformed vaccination and protein replacement strategies, yet efforts to improve their performance have focused largely on sequence engineering, nucleotide modification, and delivery vehicles. Here we show that mRNA function can be controlled by rational design of higher-order RNA architectures. We develop self-assembling mRNA origami (mRNA-OG), a class of unimolecular RNA nanostructures that encode protein-coding sequences within higher-order, programmable, and compact nucleic acid architectures. Using computational design and experimental validation, we demonstrate that mRNA-OG folds into well-defined nanostructures while remaining translationally competent in mammalian cells. Although folded mRNA-OG recruits ribosomes comparably to unfolded constructs, it produces lower protein output, indicating that RNA architecture can directly influence translational efficiency. The compact geometry of mRNA-OG also enhances encapsulation by cationic lipid delivery systems, suggesting a structural route to improved cargo packaging. Beyond its effects on translation, mRNA architecture modulates innate immune recognition. In primary human dendritic cells, folded and unfolded mRNA-OG elicit distinct cytokine programs and differential activation of stress-response pathways, including a modest induction of the integrated stress response that is not fully explained by canonical PKR signaling. Our results establish programmable structure as a new design parameter for mRNA therapeutics that can affect its functionality, delivery properties, and immune sensing.
    DOI:  https://doi.org/10.64898/2026.09.14.751315
  13. bioRxiv. 2026 Sep 20. pii: 2026.09.17.752159. [Epub ahead of print]
    Local translation couples synaptic activity to mitochondrial adaptation in dendrites.
    Madison T Jones, Natalie Noble, Robert B Darnell, Ezgi Hacisuleyman.
      Neurons rely on localized protein synthesis to rapidly adapt synaptic function to activity, yet how dendritic translation regulates mitochondrial remodeling during synaptic plasticity remains poorly understood. Here, we show that neuronal activity engages a spatially restricted translational program that couples local protein synthesis to mitochondrial function through the non-canonical translation initiation factor eIF4G2. Using proximity labeling to profile the dendritic RNA interactome, translatome, and proteome, we identify a cohort of nuclear-encoded mitochondrial mRNAs that are selectively recruited for translation following depolarization and mGluR activation. This program drives activity-dependent increases in mitochondrial membrane potential, mitochondrial abundance, and oxygen consumption. Loss of eIF4G2 abolishes these responses, whereas dendrite-specific, but not soma-restricted, rescue restores mitochondrial remodeling, demonstrating that eIF4G2 functions locally at postsynaptic sites. Mechanistically, eIF4G2 binds the 5 prime or minute untranslated regions of activity-responsive mitochondrial transcripts and promotes translation of both upstream open reading frames (uORFs) and downstream coding sequences. Using a dendritically targeted split-GFP reporter, we further show that neuronal activity induces local uORF translation to generate previously unannotated micropeptides. Together, our findings identify eIF4G2-dependent local translation as a mechanism that establishes mitochondrial competence during synaptic activity by coordinating the production of mitochondrial proteins and uORF-encoded micropeptides.
    DOI:  https://doi.org/10.64898/2026.09.17.752159
  14. RNA. 2026 Sep 22. pii: rna.081191.126. [Epub ahead of print]
    Enterovirus RNase L inhibiting RNAs are highly conserved with limited phylogenetic distribution.
    Samantha Zangari, Madeline Sherlock, Jeffrey Kieft.
      RNA molecules form specific 3D structures that facilitate a variety of functions through interactions with other macromolecules. Many RNA viral genomes maintain these structures to interact with and evade host immunity machinery. One such element, the competitive inhibitor RNA (ciRNA), discovered in the protein coding region of the poliovirus serotype 1 (PV1) genome, inhibits a host antiviral protein, ribonuclease L (RNase L). Although some functionally essential structural motifs of the PV1 ciRNA have been studied, the extent of its evolutionary conservation and other structural requirements remained unexplored. Here we combined bioinformatic and biochemical techniques to further define the requirements of a functional ciRNA and assess its phylogenetic distribution. We systematically mutated ciRNA structural features, verifying that ciRNA inhibitory activity requires a conserved loop E motif and a long-range base-pairing interaction, but its peripheral stems are dispensable and in fact a circularly permuted version maintains function. A structure-based homology search identified potential ciRNAs across the Picornaviridae family, but only a subset of those tested were functional-all are in Enterovirus coxsackiepol. When structural features needed for function were transposed from PV1 ciRNA to an RNA unable to inhibit RNase L, the chimeric RNAs did not gain wild-type function, and chemical probing data revealed that these nonfunctional RNAs are unable to form the correct secondary structure. Overall, the dual constraints of encoding a protein and forming a specific functional structure appear to not only limit the sequence diversity, but also the phylogenetic distribution, of ciRNAs.
    Keywords:  RNA structure; RNase L; chemical probing; competitive inhibitor RNA (ciRNA); enterovirus
    DOI:  https://doi.org/10.1261/rna.081191.126
  15. J Fungi (Basel). 2026 Sep 02. pii: 662. [Epub ahead of print]12(9):
    Vitamin B6 Modifies Tau-Induced Cellular Stress- and Proteostasis-Related Responses.
    Merve Yılmazer.
      Abnormal tau expression is associated with disruption of cellular homeostasis and activation of stress-response pathways. However, the effects of vitamin B6 on cellular stress responses associated with tau expression remain unclear. In this study, the influence of vitamin B6 on oxidative stress responses, endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling, autophagy-related gene expression, and apoptosis-related responses was investigated using a human tau-expressing Schizosaccharomyces pombe model. Cells expressing human tau were treated with pyridoxal 5'-phosphate (PLP), the biologically active form of vitamin B6, and changes in oxidative stress responses, endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling, autophagy-related gene expression, apoptosis-related responses, and protein carbonyl content were evaluated. Tau expression was associated with increased expression of oxidative stress-, ER stress-, and autophagy-related genes. Vitamin B6 altered several of these responses, including the expression of ER stress- and oxidative stress-related genes. Although intracellular ROS levels increased following vitamin B6 treatment, protein carbonyl levels remained largely unchanged. In contrast, apoptosis-related responses showed only limited changes. These findings show that vitamin B6 is associated with changes in selected stress- and proteostasis-related responses in tau-expressing cells. The observed effects were not uniform across all pathways, indicating a complex relationship between vitamin B6, tau expression, and cellular stress responses. This study provides further insight into cellular responses associated with tau expression and supports further investigation of vitamin B6-mediated effects in more complex experimental models.
    Keywords:  cellular stress response; fission yeast; protein tau; pyridoxal 5′-phosphate; vitamin B6
    DOI:  https://doi.org/10.3390/jof12090662
  16. Int J Biol Macromol. 2026 Sep 24. pii: S0141-8130(26)04574-5. [Epub ahead of print] 154625
    RNA derived from cancer cells as a scaffold for amyloid-β25-35 aggregation: the effect of RNA methylation and rRNA status.
    Maciej Wnuk, Olga Kołodziej, Paulina Stec, Ravikumar Kapavarapu, Agnieszka Krogul-Sobczak, Renata Wojnarowska-Nowak, Anna Lewińska.
      Besides a well-established protein aggregation-mediated pathologies in neurodegenerative diseases, protein misfolding and subsequent accumulation of non-functional aggregates may also have a role during cancer progression promoting cancer cell survival and affecting drug responses. A number of factors may modulate the process of protein aggregation. However, the role of RNA as a scaffold and its methylation status were not elucidated yet. In the present study, we have used a cellular model of cancer, namely osteosarcoma (OS) cells to investigate RNA-mediated amyloid-β (Aβ) aggregation in the biological system not related to Aβ-mediated pathology. In the presence of Aβ25-35, RNA isolated from OS cells promoted the formation of protein aggregates in a concentration-dependent manner in vitro. Drug-induced senescent OS cells devoid of two m5C RNA methyltransferases TRDMT1 and NSUN2 had limited ability to form protein aggregates. Nevertheless, this observation was associated with rRNA status and the expression of rRNA-related genes rather than RNA methylation. In contrast, RNA secreted by senescent wild type (WT) OS cells was characterized by increased m5C levels compared to RNA intracellular pools that was accompanied by its ability to stimulate the formation of Aβ25-35 aggregates. In conclusion, we show for the first time that RNA derived from cancer cells may be a scaffold promoting the formation of Aβ25-35 aggregates. More studies are needed to validate the RNA-mediated protein aggregation in cellular systems and its modulation by RNA methylation and rRNA status. RNA amyloidogenic activity should also be assessed in the presence of full-length Aβ.
    Keywords:  Amyloid-Beta; Cancer; Extracellular RNA
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154625
  17. Microorganisms. 2026 Sep 07. pii: 1972. [Epub ahead of print]14(9):
    Emerging Roles of tRNA Modifications in Translational Adaptation of Human Fungal Pathogens.
    Yuqi Zhu, Jiaqi Chen, Xinran Li, Ling Lu, Yuanwei Zhang.
      Invasive fungal infections can be life-threatening, particularly in patients with impaired immunity, yet treatment remains limited to a few antifungal drug classes. During infection, fungal pathogens encounter changes in temperature, nutrient availability, immune pressure and drug exposure that challenge their growth and survival. tRNA modifications may contribute to adaptation by supporting tRNA stability, aminoacylation and codon decoding. Studies in Aspergillus fumigatus, Candida albicans and Cryptococcus neoformans have linked conserved tRNA-modification pathways to fungal development, host interaction, stress adaptation, virulence and the response to 5-fluorocytosine, with evidence ranging from genetic and infection phenotypes to biochemical characterization of modification reactions. In this Review, we examine how these studies connect modification chemistry and substrate tRNAs with translation, protein output and infection phenotypes. We also draw on mechanistic studies from model organisms and plant-pathogenic fungi to clarify translational links that remain unresolved in human fungal pathogens. We conclude by discussing when tRNA-modification pathways become functionally limiting under host-associated conditions and how they may alter antifungal responses.
    Keywords:  Aspergillus fumigatus; Candida albicans; Cryptococcus neoformans; antifungal response; human fungal pathogens; tRNA modification; translational control; virulence
    DOI:  https://doi.org/10.3390/microorganisms14091972
  18. Curr Issues Mol Biol. 2026 Sep 03. pii: 900. [Epub ahead of print]48(9):
    Transcriptomic Reprogramming of the Human Placenta Following Maternal Opioid Exposure: Identification of Altered Metabolic and Translational Pathways.
    Po'okela K Ng, Vedbar S Khadka, Connor Howe, Jonathan Riel, Men-Jean Lee, Claire E Kendal-Wright.
       BACKGROUND: Opioid use during pregnancy is linked to preterm birth, fetal growth restriction, and Neonatal Opioid Withdrawal Syndrome. While the placenta is the primary regulator of the uterine environment, the precise molecular mechanisms by which opioids dismantle placental function remain poorly defined.
    METHODS: The transcriptomic landscape of opioid-exposed human placentas from a unique Hawai'i-based cohort was characterized.
    RESULTS: Transcriptional signatures were defined by genes involved in translational inhibition and metabolic attenuation. Integrative network modeling predicted a prominent stress-signaling hub centered on p38 Mitogen-Activated Protein Kinase and Extracellular Signal-Related Kinase 1/2, paralleling a broad suppression of ribosomal protein transcripts (Ribosomal Protein 27S, -29, and -39). This response was further characterized by the inhibition of the Myelecytomatosis Proto-Oncogene regulatory hub, predicting a loss of mitochondrial phosphate transport through associated genes (via Solute Carrier Family 25A3) and cell-cycle progression (via S-Phase Kinase-Associated Protein 1). Additionally, the genes in this model suggested upregulation of antisense regulatory brakes, such as RAP2C Antisense RNA 1, which might further reinforce this inhibitory state.
    CONCLUSION: The findings suggest that prenatal opioid exposure is associated with the disruption of placental homeostasis. This may be coordinated by protein synthesis and bioenergetic flux, as inferred from the modeled eukaryotic Translation Initiation Factor-mediated Integrated Stress Response. These findings establish a localized, clinical baseline of human placental stress, highlighting candidate molecular regulatory nodes to guide future mechanistic studies and biomarker discovery in exposed pregnancies.
    Keywords:  Ingenuity Pathway Analysis; Neonatal Opioid Withdrawal Syndrome; RNAseq; cell stress; opioid; placenta; transcriptomics
    DOI:  https://doi.org/10.3390/cimb48090900
  19. Cell. 2026 Sep 25. pii: S0092-8674(26)01065-2. [Epub ahead of print]
    Single-cell visual proteomics of a minimal bacterium reveals structural coordination of gene expression machineries.
    Joseph M Dobbs, Rasmus K Jensen, Julia Mahamid.
      Translation is a central process in gene expression. Its regulation is complex, depends on factors that include cell state and the subcellular environment, and is subject to modulation via crosstalk to processes such as transcription or translocation. Here, we used cryo-electron tomography of native and antibiotic-perturbed Mycoplasma pneumoniae cells to resolve 140 maps that recapitulate bacterial translation during the initiation, elongation, and recycling phases. We visualized multiple transcription-translation complexes, allowing us to propose a threading-based translation reinitiation mechanism and to provide structural evidence for a long-hypothesized supercomplex that coordinates transcription, translation, and membrane attachment. We resolved abundant membrane-associated large ribosomal subunits and suggest that dissociation from membranes depends on the conditional initiation of new translation, consistent with a potentially conserved mechanism in mammalian cells. This work visualizes the multilayered control of bacterial translation and demonstrates the power of in-cell structural biology to investigate regulatory circuits in gene expression.
    Keywords:  Mycoplasma pneumoniae; RNA polymerase; SecDF; cryo-electron tomography; expressome; ribosome; subtomogram analysis; transcription-translation coupling; transertion
    DOI:  https://doi.org/10.1016/j.cell.2026.08.054
  20. Recent Adv Inflamm Allergy Drug Discov. 2026 Sep 18.
    Ribotoxic Stress, ZAK Activation and the Orchestration of Inflammatory Signaling Networks in Human Disease.
    Kamlesh Sahu, Trilochan Satapathy.
       INTRODUCTION: Ribotoxic stress is an evolutionarily conserved intracellular surveillance mechanism that detects disturbances in translational fidelity and links ribosomal damage to inflammatory and stress-responsive signaling pathways. Diverse pathological stimuli, including microbial toxins, oxidative stress, metabolic dysfunction, and oncogenic translational overload, disrupt ribosome integrity and induce ribosome stalling and collision events. This review aims to summarize current advances in the molecular mechanisms underlying ribotoxic stress sensing, with particular emphasis on the ribosome-associated sterile alpha motif and leucine zipper-containing kinase (ZAK/MAP3K20), downstream Mitogen-Activated Protein Kinase (MAPK) signaling, and the contribution of ribotoxic stress to inflammation and disease pathogenesis.
    METHODS: This review was conducted as a critical narrative synthesis of the available literature. Relevant studies were identified through systematic searches of PubMed, Scopus, Web of Science, and Google Scholar databases. Experimental, structural, molecular, and translational studies investigating ribotoxic stress, ribosome collision sensing, ZAK activation, MAPK signaling, and inflammatory responses were critically evaluated using predefined inclusion and exclusion criteria.
    RESULTS: Current evidence indicates that ribosome collisions serve as central molecular triggers of ribotoxic stress signaling. Collision-induced activation of ZAK through autophosphorylation initiates p38 and JNK MAPK pathways, converting translational perturbations into coordinated transcriptional responses that regulate inflammation, apoptosis, stress adaptation and tissue remodeling. Accumulating studies demonstrate that persistent or dysregulated ribotoxic stress signaling contributes to the pathogenesis of infectious diseases, autoimmune disorders, metabolic inflammation, neurodegenerative conditions and cancer.
    DISCUSSION: The emerging understanding of ribotoxic stress highlights its role as a fundamental mechanism linking translational surveillance to innate immune and inflammatory responses. Unlike classical pathogen-recognition pathways, ribotoxic signaling detects functional disturbances in the translational machinery itself, providing an additional layer of cellular defense. The growing recognition of ZAK-mediated signaling as a central regulator of inflammatory and stress responses underscores its potential importance in disease progression and therapeutic intervention.
    CONCLUSION: Ribotoxic stress represents a critical interface between translational quality control and inflammatory signaling networks. Advances in understanding ribosome collision sensing and ZAK-dependent MAPK activation have revealed important mechanisms underlying cellular adaptation and disease development. Although several mechanistic questions remain unresolved, targeting ribotoxic stress pathways offers promising opportunities for developing novel therapies for inflammatory, immune-mediated, metabolic, and degenerative diseases.
    Keywords:  MAPK signaling; Ribotoxic stress; ZAK kinase; inflammation; ribosome collision; translational stress
    DOI:  https://doi.org/10.2174/0127722708494997260901111356
  21. Biomolecules. 2026 Aug 26. pii: 1235. [Epub ahead of print]16(9):
    Influence of Endoplasmic Reticulum Stress on Urokinase Plasminogen Activation.
    Diana Culej Bošnjak, Doris Janjić, Petra Korać, Mariastefania Antica, Maja Matulić.
      The urokinase plasminogen activator or urokinase is a highly specific extracellular protease involved in numerous physiological and pathological processes. Its activity is a consequence of its interplay with its inhibitor, PAI1, and receptor, uPAR, and is finely regulated at several levels. The aim of the work was to investigate whether endoplasmic reticulum stress can modulate urokinase activity. Two tumor cell lines grown in cell culture were treated with Thapsigargin and sodium salicylate, inducers of ER stress response. Urokinase activity was determined in the conditioned media, and expression of uPA system molecules and molecules involved in response to ER stress in cell lysates was measured. ER stress influenced urokinase activity: while in the glioblastoma line its activity was increased, in breast cancer cells it was decreased. Differences in activity were a consequence of urokinase and PAI1 expression at the protein and RNA level. However, ER stress decreased cell migration, invasion, and proliferation regardless of the changes in urokinase activity. Gene expression analysis indicated that cell specific activation of some transcription factors and pathways could be responsible for different urokinase activity regulation.
    Keywords:  endoplasmic reticulum stress; plasminogen activator inhibitor; sodium salicylate; thapsigargin; urokinase plasminogen activator
    DOI:  https://doi.org/10.3390/biom16091235
  22. Proc Natl Acad Sci U S A. 2026 Sep 29. 123(39): e2613881123
    Activity-based profiling of bacterial RNA-modifying enzymes reveals species-specific 5-methyluridine modification in Bacillus subtilis 23S rRNA.
    Qais Z Jaber, Nathan J Yu, Isao Masuda, Ya-Ming Hou, Ralph E Kleiner.
      RNA modifications play an important role in biological processes. Mapping the diversity of RNA chemistry and studying the biological function of individual modifications remains an outstanding challenge in many organisms. In particular, RNA modifications remain poorly studied across most bacterial systems. Our group previously developed RNA-mediated activity-based protein profiling (RNABPP), a reactivity-based strategy employing metabolic labeling and quantitative proteomics to profile RNA modification writer enzymes in human cells. Here, we adapt this approach to characterize RNA-modifying enzymes in bacteria. We apply metabolic labeling with 5-fluoropyrimidine nucleosides and phase separation-based enrichment of RNA-protein complexes (RNABPP-PS) to profile RNA pyrimidine modifying enzymes in Escherichia coli and Bacillus subtilis. We identify known and putative bacterial pyrimidine C5 methyltransferases, pseudouridine synthases, and dihydrouridine synthases, demonstrating the utility of our approach. Further, we find the carboxymethylaminomethyluridine (cnmn5U)-forming enzyme MnmG (GidA), supporting the existence of a covalent protein-RNA intermediate during the catalytic cycle. Finally, we use RNABPP-PS in B. subtilis to identify YfjO, an uncharacterized protein that is homologous to 5-methyluridine (m5U) methyltransferases. We use nucleoside and oligonucleotide mass spectrometry to establish that YfjO (which we rename as RlmS) installs m5U620 in the 23S rRNA (U576 in E. coli), a modification specific to the B. subtilis ribosome. We characterize ΔyfjO B. subtilis, which exhibits impaired growth and protein translation, concomitant with a defect in 70S ribosome assembly. Taken together, our study establishes a versatile platform for RNA modifying enzyme discovery and characterization in bacteria and illuminates species-specific rRNA modification chemistry in B. subtilis.
    Keywords:  RNA modifications; chemical proteomics; ribosome
    DOI:  https://doi.org/10.1073/pnas.2613881123
  23. Physiol Rep. 2026 Sep;14(18): e71115
    Long-term imoxin treatment does not attenuate disease severity in dystrophic diaphragm of male mice.
    Ji Heun Lee, Morgan E Vorwald, Melissa Roths, Joshua T Selsby, Rudy J Valentine.
      Duchenne muscular dystrophy (DMD) is characterized by chronic skeletal muscle injury and degeneration. We discovered activation of protein kinase R (PKR; EIF2AK2), a regulator of the integrated stress response, in dystrophic muscle; however, its role in DMD remains unknown. We hypothesized that the PKR inhibitor imoxin (IMX) would improve muscle force and attenuate fibrosis, inflammatory signaling, and ER stress in diaphragms from mdx mice. C57 and mdx mice were treated with vehicle or IMX for ~24 wks (0.5 mg/kg, subcutaneous, 5 times/wk). Specific force was decreased (p < 0.001), and dynamic passive force was increased (p = 0.001) by disease, but there were no IMX effects. Disease-increased fibrotic area was decreased by IMX (p = 0.038); however, IMX failed to reduce fibronectin, collagen, or TGF-β1 signaling proteins. PKR and phosphorylated (p)PKR (thr446) were increased in mdx (p < 0.001) and maintained despite IMX treatment. Similarly, PKR regulators (total PACT, pPACT (ser18), TRBP, and PP1α), and PKR substrates (total eIF2α and peIF2α (ser51)) were also increased with disease (p < 0.001), but unaffected by IMX. Likewise, IMX did not attenuate disease-mediated elevations in inflammatory signaling and ER stress markers. Overall, the dose of IMX was insufficient to attenuate PKR activation and failed to improve muscle function or prevent pathology in dystrophic skeletal muscle.
    Keywords:  DMD; Duchenne muscular dystrophy; ER stress; dystrophin; protein kinase R
    DOI:  https://doi.org/10.14814/phy2.71115
  24. Front Immunol. 2026 ;17 1922154
    Aminoacyl-tRNA synthetases in tumor immunity: canonical translation, source-resolved immune circuits and therapeutic opportunities.
    Zhipeng Zhao, Rudong Li, Siyi Wang, Xuhui Wu, Pengda Sun.
      Aminoacyl-tRNA synthetases (aaRSs) generate the aminoacyl-tRNA pool required for protein synthesis, yet selected family members also participate in nutrient sensing, stress adaptation, metabolite-dependent protein modification and extracellular immune communication. This dual biology creates a recurrent interpretive problem in cancer: an aaRS signal can reflect canonical translational demand in tumor cells, a mitochondrial program specific to immune cells, protein modification driven by lactate or amino acids, an interferon-responsive state, a secreted ligand or extracellular vesicle cargo. This review provides a mechanistic, critically appraised synthesis rather than a catalog of the aaRS family. We reconnect aminoacylation, codon-dependent translation and aaRS-specific translational stress with tumor biology and then apply a source-resolved framework based on cellular source, molecular form, localization, receiving pathway and immune output. Mechanistic strength and clinical maturity are graded independently, with direct evidence of immune function recorded separately. Representative mechanisms include substrate-specific AARS1/AARS2 lactylation, context-dependent LARS1 programs driven by codon demand, LARS2-dependent mitochondrial translation in tumor-infiltrating regulatory T cells (TI-Tregs) and regulatory B cells (Bregs), activation of Toll-like receptor 2/6 (TLR2/6) by the unique domain embedded in CARS1 (UNE-C1), WARS1 tryptophanylation intrinsic to CD8+ T cells, KARS1 and GARS1 circuits that depend on molecular form, and additional QARS1, MARS1, RARS1 and VARS1 mechanisms. Several modules show strong preclinical immune causality and human association, but none has prospective clinical validation in treated patients. aaRS-informed biomarkers and therapeutic targeting should therefore be developed as complementary, context-dependent strategies.
    Keywords:  aminoacyl-tRNA synthetases; aminoacylation; codon-dependent translation; extracellular vesicles; immunometabolism; lactylation; translational stress; tumor immunity
    DOI:  https://doi.org/10.3389/fimmu.2026.1922154
  25. Int J Mol Sci. 2026 Sep 14. pii: 8166. [Epub ahead of print]27(18):
    Reassessment of IRES Element Activity in Komagataella phaffii Using a Standardized Bicistronic System: Cryptic Promoter Activity Mimics Cap-Independent Translation.
    Danil S Kalinin, Ekaterina V Schetinina, Alexey N Fedorov, Igor E Granovsky.
      Internal ribosome entry site (IRES) elements have been proposed for constructing polycistronic mRNAs in Komagataella phaffii, but their reported activity is inconsistent and has not been evaluated under standardized conditions. Here, a standardized bicistronic EGFP-IRES-mKate2 system was developed in which the cap-dependent first cistron (EGFP) reports promoter activity, and translation of the second (mKate2) should depend on the IRES. The RhPV, TEV, PVY, and Saccharomyces cerevisiae GPR1 elements were assessed under PAOX1 and PTHI11, with EMCV and HCV as negative controls. EGFP tracked promoter induction and repression, whereas mKate2 remained at background for GPR1, EMCV, and HCV; for RhPV, TEV, and PVY it was low, promoter-independent, and persisted after promoter deletion. By RT-qPCR, the transcript was intact across both cistrons, except in the RhPV construct, where its 3' region was depleted. The residual synthesis therefore reflected cryptic promoter activity below 1% of that of PAOX1, not IRES-dependent initiation. None of the elements directed detectable cap-independent translation above 0.4% of cap-dependent expression of the same ORF, limiting their use for polycistronic expression. The system, the first to place IRES activity in K. phaffii on a quantitative scale, distinguishes IRES-dependent translation from cryptic transcription and can facilitate the search for functional elements.
    Keywords:  Komagataella phaffii; Pichia pastoris; bicistronic mRNA; cap-independent translation; cryptic promoter activity; internal ribosome entry site (IRES); polycistronic expression
    DOI:  https://doi.org/10.3390/ijms27188166
  26. Int J Mol Sci. 2026 Sep 11. pii: 8086. [Epub ahead of print]27(18):
    Mitochondrial Quality Control Imbalance in the Heterogeneity of Parkinson's Disease: From Selective Vulnerability to Stratified Transformation.
    Yongxu Chen, Chunsheng Wang.
      Parkinson's disease (PD) is a clinically and biologically heterogeneous neurodegenerative disorder in which variable symptom profiles, progression rates, and treatment responses likely reflect distinct but partially convergent pathogenic mechanisms. Among these, mitochondrial dysfunction recurs across both familial and sporadic PD; however, this broad concept alone cannot explain disease heterogeneity. To preserve mitochondrial homeostasis, cells rely on a complex mitochondrial quality control (MQC) system that encompasses protein import and proteostasis, redox surveillance, organellar dynamics and positioning, biogenesis, and selective elimination of damaged mitochondria. MQC also depends on coordination with other organelles, particularly the endoplasmic reticulum and lysosomes. In this review, we discuss how different layers of MQC maintain mitochondrial integrity and how these pathways are functionally coupled. We further consider how an MQC-based framework may help explain the clinical heterogeneity of PD, including selective neuronal vulnerability, subtype formation, and divergent disease progression, and how it can frame recent therapeutic advances aimed at biologically stratified intervention.
    Keywords:  Parkinson’s disease; heterogeneity; mitochondrial quality control; selective vulnerability; stratified transformation
    DOI:  https://doi.org/10.3390/ijms27188086
  27. Biomedicines. 2026 Aug 31. pii: 1962. [Epub ahead of print]14(9):
    Beyond m6A: The Expanding Landscape of mRNA Modifications in Renal Cell Carcinoma.
    Zongchen Hou, Diaoyi Tan, Zhiyong Xiong, Daojia Miao.
      Renal cell carcinoma (RCC) comprises molecularly diverse tumor subtypes. This diversity is reflected in distinct and adaptable gene-expression programs that enable tumor cells to reprogram metabolism and survive therapeutic pressure. By regulating RNA processing, export, stability, decay, and translation, messenger RNA (mRNA) modifications may help shape these programs. Examining mRNA modifications is therefore important for understanding metabolic adaptation and treatment resistance in RCC. This narrative review focuses on RCC studies of N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), and N4-acetylcytidine (ac4C). We focus on protein-coding transcripts and mRNA-centered mechanisms. Transcript-level studies are most extensive for m6A, while selected m5C and ac4C studies have identified defined regulator-mRNA axes. By comparison, RCC data for specific internal m7G sites in mRNA remain largely indirect. Many reported links with immune features or treatment response are based on retrospective analyses rather than treatment-specific clinical validation. Different modification pathways converge on PI3K/AKT, Hippo/YAP, metabolism, and treatment resistance, although direct molecular crosstalk has not been shown in RCC. No RNA-modification biomarker or targeted agent is used in routine RCC care. Further progress will require orthogonal site validation, broader coverage of RCC subtypes, and prospective studies conducted within contemporary treatment settings.
    Keywords:  epitranscriptomics; mRNA modification; renal cell carcinoma; therapeutic resistance
    DOI:  https://doi.org/10.3390/biomedicines14091962
  28. Commun Biol. 2026 Sep 23. pii: 1237. [Epub ahead of print]9(1):
    A human cell-free translation screen identifies the NT-2 mycotoxin as a ribosomal inhibitor that binds the peptidyl transferase center.
    Nino Schwaller, Dominic Andenmatten, Jonas Luginbühl, Julius Rabl, Helena Baur, Marc Chambon, Jonathan Vesin, Gerardo Turcatti, Evangelos D Karousis.
      Translation inhibitors are invaluable for probing ribosome function and therapeutic applications, but systematic discovery in human systems is limited by the lack of scalable, screening-compatible cell-free platforms. Here, we establish a robust high-throughput screening using human lysates that bypasses cellular cytotoxic effects. After screening ~28,000 small molecules, we identified known and a novel translation inhibitor, including NT-2, a trichothecene mycotoxin produced by the pathogenic Fusarium sporotrichioides. NT-2 suppressed protein synthesis in human cells and yeast lysates, while sparing translation in bacteria and intact yeast cells. Cryo-EM at 1.76 Å revealed NT-2 bound at the peptidyl transferase center of the human 60S ribosome. In addition, cryoEM classification of NT-2 treated cells shows ribosomes in an inactive eEF2/SERBP1-bound dormant state. Together, these results expose NT-2 as a previously unrecognized environmental inhibitor of mammalian protein synthesis and demonstrate the power of cell-free translation screening to reveal new inhibitors with unexpected ribosome fates.
    DOI:  https://doi.org/10.1038/s42003-026-10743-6
  29. Mol Biol Rep. 2026 Sep 23. pii: 1612. [Epub ahead of print]53(1):
    Targeting the METTL5-MGST1 axis for cancer therapy: molecular mechanisms and therapeutic implications.
    Abinash Nayak, Sudhansu Sekhar Nishank.
      The epitranscriptomic regulation of cancer represents one of the most rapidly expanding frontiers in oncology. Among the newly characterized epigenetic axes, the Methyltransferase-like protein 5-Microsomal Glutathione S-Transferase 1 (METTL5-MGST1) signaling axis has emerged as a mechanistically compelling circuit implicated in tumor progression, ferroptosis resistance, immune evasion, and treatment-refractory behavior, most directly established in hepatocellular carcinoma and increasingly recognized, though through varying and not always MGST1-dependent mechanisms, across other cancer types. METTL5, a ribosomal 18S rRNA N6-methyladenosine (m6A) methyltransferase stabilized by its obligate cofactor tRNA methyltransferase activator subunit 11-2 (TRMT112), orchestrates oncogenic mRNA translation by methylating adenosine 1832 (A1832) in the 18S ribosomal RNA decoding center. Among its downstream effectors, Microsomal Glutathione S-Transferase 1 (MGST1) has been identified as a key mediator of ferroptosis suppression and redox homeostasis, enabling cancer cells to resist lipid peroxidation-driven cell death and conventional therapies. This review comprehensively examines the structural biology, expression patterns, molecular mechanisms, and cancer-type-specific functions of both METTL5 and MGST1, with particular emphasis on their functional interdependence. We further discuss downstream signaling cascades including c-Myc/FBXW7, TGF-β/SMAD, Akt/GSK-3β, Nrf2/SLC7A11, and the ATF4/ferroptosis axis. The therapeutic implications of targeting this axis mainly through small-molecule inhibitors, RNA interference, CRISPR strategies, and immunotherapy combinations are critically evaluated. Understanding the METTL5-MGST1 axis provides a compelling rationale for novel combination strategies against therapy-resistant cancers.
    Keywords:  18S rRNA methylation; Cancer therapy; Ferroptosis; Hepatocellular carcinoma; METTL5; MGST1; m6A
    DOI:  https://doi.org/10.1007/s11033-026-12757-z
  30. J Dev Biol. 2026 Sep 03. pii: 40. [Epub ahead of print]14(3):
    Diaphragmatic Mitochondrial Myopathy in a Patient-Derived Mouse Model of Barth Syndrome.
    Kristen Tentler, Paige L Snider, Catalina Matias, Jeffrey J Brault, Simon J Conway.
      Barth syndrome (BTHS) is a rare, X-linked genetic disorder caused by mutations in the enzyme TAFAZZIN (TAZ), resulting in insufficient cardiolipin (CL) remodeling and mitochondrial dysfunction. While BTHS respiratory distress and breathing difficulties are commonly reported, the precise role of intrinsic respiratory tissue vulnerabilities has only recently begun to be appreciated. Historically, BTHS respiratory distress is frequently attributed to secondary consequences like cardiomyopathy or generalized skeletal myopathy, leaving the intrinsic vulnerability of vital respiratory muscles poorly understood. Using a patient-tailored point mutant knock-in mouse model (TazPM) harboring a stable but enzymatically deficient TazD75H protein, we investigated the autonomous physiological and metabolic responses in the diaphragm and lungs. Contrary to the paradigm that respiratory muscles are unaffected, TazPM diaphragms exhibit structurally abnormal mitochondria and undergo a survival-critical, bifurcated compensatory remodeling response to prevent fatal respiratory failure under severe bioenergetic stress. The TazPM adaptive mechanism is orchestrated by chronic activation of the mitochondrial Integrated Stress Response (ISR) via the Gcn2/eIF2α signaling pathway. This stress pathway halts global translation to conserve cellular ATP at the expense of reduced NAD+ levels, while selectively upregulating defensive mitokines and metabolic sirtuins and structural muscle remodeling. Furthermore, the TazPM diaphragm transitions into a highly specialized, slow-twitch motor system that is expected to reduce the energy cost per contraction. Concurrently, despite TazPM lungs exhibiting structurally abnormal mitochondria, they resist generalized mitochondrial collapse despite ADP reduction, executing tissue-specific metabolic reprogramming and localized biochemical adaptations to sustain respiratory homeostasis.
    Keywords:  Barth syndrome; CRISPR/Cas mouse model; bioenergetics; diaphragmatic mitochondrial myopathy; tafazzin
    DOI:  https://doi.org/10.3390/jdb14030040
  31. Genes (Basel). 2026 Aug 22. pii: 984. [Epub ahead of print]17(9):
    Alternative RNA Splicing in Cancer: Molecular Mechanisms, Functional Consequences, Biomarkers and Therapeutic Opportunities.
    Quanyou Wu, Kai Gui.
      Alternative pre-mRNA splicing is a central layer of gene regulation that enables a limited number of genes to generate a far larger and more context-dependent transcriptome and proteome. In cancer, splicing is disrupted by mutations in cis-regulatory sequences, recurrent lesions in spliceosome components, altered abundance or activity of RNA-binding proteins, and changes in transcription, chromatin, RNA modification, metabolism and stress signalling. These alterations are not merely by-products of malignant transformation. They can create oncogenic protein isoforms, eliminate tumour-suppressive products, remodel cellular identity, promote metastasis and drug resistance, and generate tumour-restricted peptides that are visible to the immune system. Large pan-cancer datasets, long-read sequencing, single-cell isoform profiling, proteogenomics and functional perturbation screens are now resolving this complexity at unprecedented scale. In parallel, multiple therapeutic strategies are advancing, including modulators of the SF3B complex, molecular glues that degrade RBM39, inhibitors of protein arginine methyltransferases and splicing kinases, splice-switching oligonucleotides, programmable RNA-targeting systems, and vaccines or T-cell receptors directed against splicing-derived neoantigens. This review integrates the molecular logic of splice-site selection with the cancer-specific mechanisms that perturb it, summarizes representative isoform switches across the hallmarks of cancer, evaluates emerging technologies and clinical biomarkers, and discusses the opportunities and constraints of translating splicing biology into precision oncology. Particular emphasis is placed on tumour specificity, intratumoural heterogeneity, proteomic validation, therapeutic windows and rational combination strategies.
    Keywords:  RNA-binding proteins; alternative splicing; antisense oligonucleotides; cancer; spliceosome
    DOI:  https://doi.org/10.3390/genes17090984
  32. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2026 Jul 28. pii: 1672-7347(2026)07-1303-16. [Epub ahead of print]51(7): 1303-1318
    [NPLOC4 promotes proliferation, invasion, and migration of hepatocellular carcinoma cells via enhancing Wnt/β-catenin-mediated mitophagy].
    Shuai Liang, Zichuan Lu, Zhongcheng Zhu, Tiantian Tang, Ke Ye.
       OBJECTIVES: Dysregulation of mitophagy contributes to the initiation and progression of hepatocellular carcinoma (HCC). Nuclear protein localization 4 homolog (NPLOC4) is an essential protein involved in various cellular processes and has been implicated in multiple cancers. Recent studies have suggested that NPLOC4 participates in the regulation of mitophagy; however, its role in HCC remains unclear. This study aims to investigate the role of NPLOC4 in mitophagy and its underlying regulatory mechanisms in HCC.
    METHODS: RNA sequencing data from the GSE277232 and GSE251942 datasets obtained from the Gene Expression Omnibus (GEO) database were analyzed together with mitophagy-related genes collected from the GeneCards database to identify differentially expressed mitophagy-related genes in HCC. NPLOC4 expression was further analyzed and validated by Western blotting. Small interfering RNA (siRNA)-mediated knockdown of NPLOC4 was performed in HCC cells for functional loss-of-function assays. Mitophagy levels were evaluated by analyzing the expression of mitophagy-related proteins, transmission electron microscopy, and immunofluorescence staining.
    RESULTS: Bioinformatics analysis identified NPLOC4 as a key differentially expressed mitophagy-related gene. NPLOC4 was significantly upregulated in HCC tissues and was associated with poor clinical prognosis (all P<0.05). Knockdown of NPLOC4 inhibited HCC cell proliferation, migration, and invasion, while promoting apoptosis (all P<0.05). In addition, NPLOC4 knockdown suppressed mitophagy and the Wnt/β-catenin signaling pathway in HCC cells (all P<0.05). Treatment with the Wnt agonist BML-284 abolished the inhibitory effect of NPLOC4 knockdown on mitophagy (P<0.05), indicating that NPLOC4 regulates mitophagy through activation of the Wnt/β-catenin pathway. Furthermore, treatment with the mitophagy inducer carbonyl cyanide m-chlorophenyl hydrazone (CCCP) reversed the inhibitory effects of NPLOC4 knockdown on HCC cell proliferation, migration, and invasion (all P<0.05), suggesting that NPLOC4 silencing suppresses HCC progression by regulating mitophagy.
    CONCLUSIONS: NPLOC4 is highly expressed in HCC. Downregulation of NPLOC4 inhibits activation of the Wnt/β-catenin signaling pathway, thereby inhibiting mitophagy and ultimately inhibiting HCC cell proliferation, migration, and invasion. These findings suggest that NPLOC4 may serve as a potential biomarker and therapeutic target for HCC.
    Keywords:  NPLOC4; hepatocellular carcinoma; invasion; migration; mitophagy; proliferation
    DOI:  https://doi.org/10.11817/j.issn.1672-7347.2026.260157
  33. Nat Commun. 2026 Aug 24. pii: 10101. [Epub ahead of print]17(1):
    TOR-NOT4 signalling couples translation to co-translational quality control in plants.
    Maximillian A Schwarze, Rory Osborne, Margot Raffeiner, Manuel González-Fuente, Anastasia Kanali, Mark Bailey, Ross D Etherington, Lina Zhou, Suayib Üstün, Daniel J Gibbs.
      Protein synthesis must be tightly coordinated with quality control to prevent proteotoxic stress, yet the mechanisms underlying co-translational surveillance in plants, and how these are aligned with translational output, remain poorly understood. Here, we identify three NOT4-like E3 ubiquitin ligases in Arabidopsis thaliana as regulators of co-translational protein quality control and uncover a functional link between NOT4 and TARGET OF RAPAMYCIN (TOR) signalling that coordinates quality-control capacity with translational output. Loss of NOT4 function increases basal TOR activity and global translation rates, resulting in the accumulation of polyubiquitylated proteins and heightened sensitivity to proteasome inhibition, TOR inhibition, and protein misfolding stress. Consistent with prior evidence that NOT4 proteins are TOR-regulated phosphotargets, not4 mutants also phenocopy TOR-inhibited wild-type plants for a subset of transcriptional and growth-related processes. Furthermore, elevated translation in NOT4-deficient plants enhances resistance to Pseudomonas syringae pv. tomato. Collectively, our findings reveal a functional coupling between TOR signalling and NOT4 activity that may scale quality control with translational demand to safeguard proteome homoeostasis across eukaryotes.
    DOI:  https://doi.org/10.1038/s41467-026-77200-0
  34. Redox Biol. 2026 Sep 16. pii: S2213-2317(26)00404-0. [Epub ahead of print]97 104405
    Dual promoter architecture of NFE2L2 underlies isoform-specific translational control of NRF2.
    Alicja Sznarkowska, Zuzanna Urban-Wójciuk, Alicja Dziadosz-Brzezińska, Maciej Cieśla, Sara Kusiński, Kevork Wakimian, Alicja Szabelska-Beręsewicz, Elżbieta Chruściel, Ines Papak, Natalia Marek-Trzonkowska, Artur Piróg, Witold Rzyman.
      Transcription factor NRF2 (encoded by the NFE2L2 gene) is a central signalling hub that coordinates antioxidant, detoxification, anti-inflammatory and metabolic programmes to maintain cellular homeostasis, with broad relevance to degenerative diseases, chronic inflammation and cancer. NFE2L2 is transcribed from two promoters: the canonical promoter (P1) and an alternative promoter (P2), generating transcripts that differ solely in their first exon. Exon 1 of P1-derived transcripts contains the AUG start codon, whereas the considerably longer exon 1' of P2-derived transcripts forms an extended 5' untranslated region (5'UTR). Consequently, the P1-derived NRF2 isoform 1 contains 16 additional N-terminal amino acids relative to the P2-derived isoform 2. Although transcripts from both promoters are expressed in human tissues, the existence of isoform 2 protein and the functional significance of alternative promoter usage have remained unresolved. Here, we identify an endogenous NRF2 protein species consistent with isoform 2 using an isoform-specific siRNA strategy. Isoform 2 is negatively regulated by KEAP1 and retains the ability to activate canonical NRF2 target genes. Despite similar stability of the two isoforms, isoform 2 accumulates at substantially lower basal levels, which is associated with reduced translational engagement of P2-derived transcripts. Polysome profiling revealed that P1-derived transcripts are predominantly associated with polysomes, whereas P2-derived transcripts are distributed between polysomal and subpolysomal fractions. The extended P2-specific 5'UTR contains evolutionarily conserved structural features that may contribute to translational regulation. Finally, the electrophilic NRF2 activator omaveloxolone (RTA-408) induced translation of transcripts from both promoters, demonstrating that NRF2 stress response is coordinated through the combined regulation of mRNA translation and protein stability.
    Keywords:  NFE2L2 transcripts; NRF2 isoforms; Omaveloxolone; Polysome profiling; RTA-408; Translation regulation
    DOI:  https://doi.org/10.1016/j.redox.2026.104405
  35. Sci Adv. 2026 Sep 25. 12(39): eaef0902
    TANGO6 coordinates transcription and translation through nucleocytoplasmic partitioning.
    Gonzalo Bigliani, Cecilia Ballaré, Jose Wojnacki, Stefania Androulaki, Tanit Guitart, Enrique Blanco, Ombretta Foresti, Agustin Lujan, Yamile Ana, Fátima Gebauer, Luciano Di Croce, Vivek Malhotra.
      Coordinated RNA and protein synthesis is fundamental to cell function and survival. Here, we show that TANGO6, a nucleocytoplasmic RNA binding protein, is an integral component of the proteostasis control axis, regulating both transcription and translation. In the nucleus, TANGO6 is recruited to gene promoters alongside RNA polymerase II, where it controls the transcriptional activation of essential genes, including those required for G1-S cell cycle progression and cell differentiation. Cytoplasmic TANGO6 associates with polysomes to promote protein synthesis. Under stress conditions, the organization of TANGO6 changes; notably, heat stress triggers its translocation to the nucleus, thereby depleting its cytoplasmic pool. Thus, TANGO6 assists in both transcriptional and translation reprogramming to support cell survival. Overall, the nucleocytoplasmic shuttling of TANGO6 is a central mechanism for controlling the cellular proteome, establishing its essential role in cell viability from homeostasis to stress adaptation.
    DOI:  https://doi.org/10.1126/sciadv.aef0902
  36. Planta. 2026 Sep 25. pii: 140. [Epub ahead of print]264(5):
    Kinase crosstalk coordinates stress adaptation and metabolic homeostasis in plants.
    Teja Manda, Delight Hwarari, Raphael Dzinyela.
       MAIN CONCLUSION: Crosstalk among MAPKs, CDPKs, SnRKs, and TOR establishes a dynamic regulatory framework that balances energy homeostasis, defense, and development under stress conditions. Continued advances in systems biology and functional genomics will further clarify these complex interactions and accelerate the development of crops with enhanced stress resilience, growth stability, and resource-use efficiency. Plants rely on complex kinase signaling networks to sense, integrate, and respond to rapidly fluctuating environmental stresses. Central to these networks are mitogen-activated protein kinases (MAPKs), calcium-dependent protein kinases (CDPKs), sucrose non-fermenting-1-related kinases (SnRKs), and the Target of Rapamycin (TOR) complex, which collectively coordinate stress perception, metabolic regulation, and growth adaptation. Although the individual functions of these pathways have been extensively characterized, a unified mechanistic framework describing their interconnected roles across diverse stress conditions remains incomplete. Here, we synthesize recent advances in plant stress signaling to propose an integrated model of kinase crosstalk that highlights key nodes of convergence, reciprocal regulation, and metabolic-hormonal integration. We emphasize the antagonistic interplay between SnRK1 and TOR as a central regulatory hub controlling energy balance and stress adaptation, while MAPK and CDPK cascades intersect with SnRK1-mediated autophagy and TOR-dependent anabolic growth pathways. In addition, hormonal signaling networks involving abscisic acid (ABA), salicylic acid (SA), and jasmonic acid (JA) provide further layers of regulatory coordination that improve cellular responses to environmental stress. Collectively, these interconnected kinase networks orchestrate survival strategies, metabolic homeostasis, and resilience under adverse conditions. By integrating these signaling modules into a systems-level framework, this review provides mechanistic insights and emerging perspectives for engineering crops with enhanced stress tolerance, growth stability, and energy-use efficiency.
    Keywords:  Calcium signaling; Drought; Heat; Kinase families; Phosphoproteomics; Salinity
    DOI:  https://doi.org/10.1007/s00425-026-05177-7
  37. Rev Med Virol. 2026 Sep;36(5): e70204
    Epitranscriptomic Regulation in Oncogenic Viruses: Emerging Roles of RNA Modifications in Viral Persistence and Tumourigenesis.
    Zinan Yang, Yang Bai, Lihui Jia, Ying Zhang, Qiang Sun.
      Oncogenic viral pathogens, such as human papillomavirus (HPV), Epstein-Barr virus (EBV), hepatitis B and C viruses (HBV, HCV), and Kaposi's sarcoma-associated herpesvirus (KSHV), are involved in a significant proportion of human cancers worldwide. While genetic and epigenetic mechanisms underlying viral oncogenesis have been thoroughly investigated, emerging evidence underscores a critical role for epitranscriptomic regulation in virus-host interactions and their clinical consequences. RNA modifications such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), and pseudouridine (Ψ) dynamically modulate RNA stability, translation, and immune recognition, thereby regulating viral replication and persistence. The present review describes current knowledge on the epitranscriptomic landscape of oncogenic viral pathogens and its functional implications. This review discusses how viral and host transcripts are selectively modified by cellular writers, erasers, and readers, shaping key stages of the viral life cycle, including replication, latency, and reactivation. Particular emphasis is placed on the role of RNA modifications in maintaining chronic infection and promoting tumourigenesis through the regulation of oncogenic pathways, cell proliferation, and apoptosis. Additionally, the present review examines how epitranscriptomic marks contribute to immune evasion by altering innate immune sensing and interferon responses. Finally, it explores the therapeutic potential of targeting epitranscriptomic machinery, highlighting recent advances in small-molecule inhibitors and the challenges associated with specificity and off-target effects. A deeper understanding of epitranscriptomic regulation in oncogenic viruses may reveal novel biomarkers and therapeutic strategies for virus-linked malignancies.
    Keywords:  RNA modifications; cancer; epitranscriptomic; oncogenic viruses; tumourigenesis
    DOI:  https://doi.org/10.1002/rmv.70204
  38. Cell Biochem Funct. 2026 Sep;44(9): e70303
    Clerodendrum japonicum Extract Suppresses the Pathogenicity of Rheumatoid Arthritis Fibroblast-Like Synoviocytes by Inhibiting METTL3-Mediated ICAM2 mRNA Methylation.
    Ying Huang, JiangCun Wei, Yan Ma, XiaoPing Mei, MingTao Huang, Liang Lu, JianLong Zhou, ZuJie Qin.
      Clerodendrum japonicum (Thunb.) Sweet (Clerodendrum japonicum) is a traditional medicinal plant with reported anti-inflammatory use, but its anti-rheumatoid arthritis (RA) activity and molecular basis remain insufficiently characterized. Activated fibroblast-like synoviocytes (FLSs) contribute to persistent inflammation and joint destruction in rheumatoid arthritis (RA). This study investigated whether extracts of Clerodendrum japonicum attenuate pathogenic RA-FLS phenotypes and examined the possible involvement of METTL3-dependent N6-methyladenosine (m6A) regulation of ICAM2 mRNA. Tumor necrosis factor-α-stimulated human RA-FLSs (MH7A cell line) were used as an in vitro model to evaluate the anti-RA effects of Clerodendrum japonicum extracts. Cell proliferation, apoptosis, migration, invasion, and inflammatory cytokine secretion were evaluated. The underlying mechanisms were further investigated using real-time quantitative polymerase chain reaction, Western blot, and RNA immunoprecipitation. In addition, a collagen-induced arthritis (CIA) mouse model was employed to validate the anti-RA effects of the extracts in vivo. Drug-containing serum derived from Clerodendrum japonicum extracts attenuated TNF-α-induced proliferation, migration, invasion, and pro-inflammatory cytokine release in MH7A cells while increasing apoptosis. The ethyl acetate fraction (CJEA) produced the most pronounced effects among the tested fractions. CJEA-containing serum reduced global m6A abundance and METTL3 expression. METTL3 overexpression partially reversed the cellular effects associated with CJEA-containing serum. METTL3 knockdown reduced m6A enrichment and stability of ICAM2 mRNA, whereas METTL3 or ICAM2 overexpression partially restored ICAM2 expression and pathogenic RA-FLS phenotypes. Oral CJEA also reduced clinical and histological arthritis severity in CIA mice and was associated with lower synovial METTL3 and ICAM2 expression. Our findings support the involvement of METTL3-dependent m6A regulation of ICAM2 mRNA in the response of RA-FLSs to CJEA-containing serum. CJEA may attenuate pathogenic RA-FLS behavior and experimental arthritis at least partly through modulation of this pathway. Because the active constituent(s), direct molecular target, pharmacokinetics, and comprehensive safety profile remain undefined, further chemical and pharmacological validation is required.
    Keywords:  Clerodendrum japonicum; ICAM2; METTL3; fibroblast‐like synoviocytes (FLSs); rheumatoid arthritis (RA)
    DOI:  https://doi.org/10.1002/cbf.70303
  39. Viruses. 2026 Sep 15. pii: 1021. [Epub ahead of print]18(9):
    Viral Strategies and Cellular Countermeasures That Regulate mRNA Access to the Translation Apparatus: Second Edition.
    Christopher U T Hellen.
      Viruses depend on the cellular translation apparatus, and the translation process is consequently a focus for competing mechanisms to promote and to restrict viral translation [...].
    DOI:  https://doi.org/10.3390/v18091021
  40. Microorganisms. 2026 Sep 16. pii: 2073. [Epub ahead of print]14(9):
    Proteomic Profiling Reveals Intracellular Regulatory Network Disturbance Induced by QseB Deletion in Glaesserella parasuis.
    Xuefeng Yan, Congwei Gu, Mingde Zhao, Lvqin He.
      The highly conserved QseB/QseC two-component system (TCS) in Glaesserella parasuis (G. parasuis) regulates gene expression, with QseC as a histidine kinase and QseB as a response regulator. This study employed data-independent acquisition (DIA) quantitative proteomics to investigate the effects of qseB deletion on bacterial morphology, proteome, and molecular regulation. Electron microscopy revealed that the ΔqseB mutant exhibited ultrastructural damage, including cell shrinkage, membrane impairment, cell wall separation, and protoplast dissolution, indicating that the loss of qseB resulted in severe compromise of cellular structural integrity. A total of 1493 proteins were identified by DIA quantitative proteomics. Fifty-five proteins were differentially expressed between the ΔqseB mutant and the wild-type strain SC1401. Among them, 24 were upregulated and 31 were downregulated. Upregulated proteins were mainly heat shock proteins (DnaK, HslV/U, ClpB), molecular chaperones (GroL, HtpG, HslO), and co-chaperone GroES, along with translation inhibitors RaiA and RsfS. These proteins participate in stress response, protein folding, and proteostasis maintenance. The downregulated proteins included QseC, LolB, CarB, ThiL, and Tgt, which are linked to TCSs, quorum sensing, and transport functions. KEGG analysis indicated that the differentially expressed proteins are involved in RNA degradation, amino acid metabolism, and ABC transporters. Protein-protein interaction (PPI) network analysis identified 10 core hub proteins, including GroEL, HslU, and QseC. These proteins may play key roles in maintaining cellular homeostasis. Integrated multi-omics analysis identified three genes (dnaK, hslU, hslO) that were differentially expressed in both transcriptomic and proteomic data. qRT-PCR results confirmed these findings. In summary, loss of qseB disrupts the QseB/QseC system. This affects stress response, metabolism, and cell structure. These changes may affect bacterial fitness and host adaptation, providing clues for understanding the pathogenic mechanisms of G. parasuis.
    Keywords:  DIA quantitative proteomics; G. parasuis; QseB; scanning electron microscopy; transmission electron microscopy
    DOI:  https://doi.org/10.3390/microorganisms14092073
  41. Pharmaceuticals (Basel). 2026 Sep 05. pii: 1402. [Epub ahead of print]19(9):
    Natural Small Molecules Targeting Mitochondrial Quality Control for the Treatment of Metabolic Diseases: Mechanisms, Novel Formulations, and Translational Perspectives.
    Chongyan Zhao, Yuan Gao, Ting Zhou, Lei Sun, Qingsong Qu.
      Metabolic diseases are jointly driven by insulin resistance, chronic inflammation, lipotoxicity, and disrupted organelle homeostasis arising from sustained nutrient overload. These disorders substantially increase the risk of cardiovascular, renal, and other multi-organ complications and have become a major global public health burden. Mitochondria are central organelles that integrate energy metabolism with stress signaling. They participate in fatty acid β-oxidation, the tricarboxylic acid cycle, and oxidative phosphorylation, while also regulating reactive oxygen species generation, mitochondrial DNA-related inflammatory signaling, calcium homeostasis, and cell death. Under chronic metabolic stress, the mitochondrial quality control (MQC) system shifts from adaptive repair toward decompensation, characterized by impaired mitochondrial biogenesis, abnormal mitochondrial dynamics, defective mitophagy, disrupted proteostasis and mitochondrial unfolded protein response, increased oxidative stress, and impaired metabolic reprogramming. Natural small molecules possess structural diversity and multi-target, multi-pathway regulatory properties. They can modulate multiple MQC processes and improve mitochondrial function and metabolic phenotypes in preclinical models. Novel formulations, structural optimization, and mitochondria-targeted delivery can further improve their solubility, bioavailability, tissue exposure, and subcellular localization, thereby enhancing therapeutic efficacy and translational potential. This review systematically summarizes the mechanisms of MQC dysregulation in metabolic diseases, the evidence supporting natural small-molecule interventions, and strategies for formulation and delivery optimization. Future studies should strengthen causal validation of MQC, quantify intramitochondrial drug exposure, and incorporate clinically relevant endpoints to facilitate the translation of natural small-molecule MQC modulators.
    Keywords:  metabolic diseases; mitochondria; mitochondrial quality control; mitochondrial targeting strategy; natural small molecules
    DOI:  https://doi.org/10.3390/ph19091402
  42. Angiogenesis. 2026 Sep 23. pii: 70. [Epub ahead of print]29(4):
    YTHDF3 promotes angiogenesis in endometriosis by enhancing the translation efficiency of PFKFB3.
    Xiaosa Li, Jiale Wang, Liang Yuan, Yuqi Wang, Jinzhi Wei, Ping Li, Runxin Wang, Xingyan Xu, Qiuwen Mai, Junxiu Liu, Huiping Lin, Xiaodong Fu.
      Angiogenesis plays a critical role in the progression of endometriosis, with enhanced glycolysis accelerating pathological angiogenesis. Prior research has identified a central role for N6-methyladenosine (m6A) modification in regulating glycolytic processes. This study investigates the involvement of m6A-mediated mechanisms in the regulation of glycolysis and angiogenesis in endometriosis. Here, we report that PFKFB3 is significantly upregulated in vascular endothelial cells of ectopic endometrial tissues from humans and mice, correlating with elevated expression of YTHDF3. Specific deletion of Ythdf3 in endothelial cells reduces PFKFB3 protein levels and suppresses angiogenesis in ectopic endometrial lesions. Mechanistically, PFKFB3 mRNA displays increased m6A modifications in endometrial microvascular endothelial cells (EMECs). METTL3 enhances m6A modification of PFKFB3 mRNA, which is recognized by YTHDF3, promoting PFKFB3 translation and glycolytic activity, thus facilitating tube formation, migration, and proliferation of ovarian microvascular endothelial cells (OMECs). Moreover, estrogen upregulates both METTL3 and PFKFB3 via the estrogen receptor ERα. Collectively, these findings establish the YTHDF3-m6A-PFKFB3 pathway as a critical driver of angiogenesis in endometriosis, suggesting that targeting this pathway represents a promising therapeutic strategy.
    Keywords:  Angiogenesis; Endometriosis; Glycolysis; N6-methyladenosine; PFKFB3; YTHDF3
    DOI:  https://doi.org/10.1007/s10456-026-10095-z
  43. Curr Issues Mol Biol. 2026 Aug 27. pii: 869. [Epub ahead of print]48(9):
    URMylation Signaling Pathway in Cancer: Molecular Mechanisms and Therapeutic Opportunities.
    Jingchao Wang, Peiqiang Yan, Weiwei Jiang, Li Chen, Daoyuan Huang, Tao Hou, Hiroyuki Inuzuka, Wenyi Wei.
      Ubiquitin-related modifier 1 (URM1) defines a distinctive ubiquitin-like system in which URM1 functions both as a covalent protein modifier and a sulfur carrier required for wobble uridine (U34) thiolation of cytosolic tRNAs. This dual role places URM1 signaling at the intersection of protein post-translational modification and codon-sensitive translational control. Although URM1 remains less well characterized than ubiquitin and other ubiquitin-like modifiers, accumulating evidence links URM1-associated processes to oxidative-stress tolerance, proteostasis, and tumorigenesis. In this review, we summarize the molecular architecture and biochemical regulation of URM1 signaling, distinguish the biological significance of protein URMylation from URM1-dependent tRNA U34 thiolation, and evaluate evidence connecting these pathways to cancer biology. Notably, stress-inducible protein URMylation has been demonstrated in mammalian cells, although endogenous mammalian URM1 substrates and their cancer-relevant functions remain incompletely defined to date. In parallel, URM1-dependent tRNA thiolation has been linked to selective translational programs that support metastatic progression and adaptation to targeted therapy. We further discuss emerging therapeutic opportunities associated with redox and translational dependencies, as well as the potential limitations and challenges of pathway selectivity, biomarker development, and normal-tissue toxicity. Together, these studies position URM1 signaling as a context-dependent stress-adaptive network with emerging relevance to cancer biology and precision oncology.
    Keywords:  MOCS3; URM1; URMylation; cancer therapy; oxidative stress; proteostasis; tRNA thiolation
    DOI:  https://doi.org/10.3390/cimb48090869
  44. Neurosci Biobehav Rev. 2026 Sep 19. pii: S0149-7634(26)00450-1. [Epub ahead of print]191 106993
    Translational dysregulation as a mechanistic driver of cognitive, behavioral, and affective phenotypes in FXS and TSC.
    Saheed Lawal, Moniza Mujtaba, Prerana Shrestha.
      Neurodevelopmental disorders (NDDs) are characterized by a spectrum of cognitive, behavioral, and affective morbidities, reflecting underlying disruptions in neural circuit development. Emerging evidence implicates translational dysregulation of synaptic proteins as a central mechanistic driver of these disordered phenotypes. Translational dysregulation entails atypical mechanisms of impaired initiation, elongation, and mRNA targeting, causing imbalanced protein synthesis. In NDDs specifically, translation of synaptic proteins is perturbed across developing neurons. Tuberous Sclerosis Complex (TSC) and Fragile X Syndrome (FXS) are notable monogenic NDDs, in which mutations in regulatory genes (Tsc1/Tsc2 in TSC, Fmr1 in FXS) disrupt signaling pathways that converge on mTORC1, PERK, and ERK/MAPK proteins, and result in excessive or insufficient translation of key synaptic proteins. These translational imbalances eventually compromise synapse formation, dendritic spine maturation, and neuronal network connectivity, contributing to deficits in learning, memory, social behavior, and emotional regulation. This review highlights the molecular mechanisms by which aberrant protein synthesis contributes to the cognitive and behavioral manifestations of TSC and FXS. Importantly, we also highlight cell-type-specific mechanisms, illustrating how translational dysregulation differentially impacts distinct neuronal and glial populations to shape behavioral and cognitive outcomes. Understanding the links between translational control and neurodevelopmental outcomes provides critical insights into the pathophysiology of these disorders and informs the development of targeted therapeutic interventions aimed at restoring synaptic protein homeostasis.
    Keywords:  Affective behavior; Cognition; Emotional dysregulation; FMRP Tuberous Sclerosis Complex; FXS; Fragile X Syndrome; Protein synthesis; Tsc1; Tsc2 Translational control; mRNA translation Neurodevelopmental process Synaptic plasticity Behavior
    DOI:  https://doi.org/10.1016/j.neubiorev.2026.106993
  45. Biochem Biophys Res Commun. 2026 Sep 17. pii: S0006-291X(26)01355-0. [Epub ahead of print]837 154589
    USP19 protects against cigarette smoke-induced lung injury and epithelial stress.
    Atsushi Miyamoto, Kiyoshi Uemasu, Xiuying Li, Kazuya Tanimura, Simon S Wing, Toru Nyunoya.
      Cigarette smoke (CS) imposes substantial proteostatic stress on lung epithelial cells, yet the protein quality control mechanisms that determine susceptibility to injury remain incompletely understood. We investigated the role of the ubiquitin-specific protease 19 (USP19) in CS-related lung injury across human lung tissue, a chronic CS-exposure mouse model, and cigarette smoke extract (CSE)-treated bronchial epithelial BEAS-2B cells. USP19 protein abundance was reduced in lung tissue from patients with severe COPD. Usp19-deficient mice developed greater CS-induced airspace enlargement compared to wild-type mice. In BEAS-2B cells, CSE reduced USP19 abundance, and USP19 knockout increased CSE-induced apoptosis. In addition, re-expression of USP19 partially restored viability. USP19 deficiency altered the temporal profile of integrated stress response signaling, culminating in enhanced CHOP induction, and CHOP (DDIT3) knockdown partially rescued CSE-induced loss of viability. USP19-deficient cells also showed a decrease in p62 abundance, puncta number, and area during CSE exposure, suggesting altered p62-associated protein handling. Together, these findings identify USP19 as a protective modifier of CS-related lung injury and epithelial stress, consistent with a role in supporting the capacity of lung epithelial cells to accommodate CS-induced proteostatic stress.
    Keywords:  CHOP; Chronic obstructive pulmonary disease; Cigarette smoke; Integrated stress response; Proteostasis; USP19
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154589
  46. Tidsskr Nor Laegeforen. 2026 Sep 22. 146(11):
    Lost in translation – moralsk stress eller moralsk belastning?
    Ingrid Miljeteig, Helge Alsaker Solheim.
      
    DOI:  https://doi.org/10.4045/tidsskr.26.0478
  47. MedComm (2020). 2026 Sep;7(9): e70962
    METTL3-Mediated N6-Methyladenosine Modification Activates the EGR1-ZBP1 Axis to Promote PANoptosis-Like Cardiomyocyte Death in Myocardial Ischemia-Reperfusion Injury.
    Linnan Li, Jinfeng Gao, Xiaoxue Zhang, Kunming Dai, Hao Cheng, Jianying Ma, Junbo Ge.
      Myocardial ischemia-reperfusion (I/R) injury is a major cause of cardiac dysfunction, but the mechanisms linking metabolic stress to regulated cardiomyocyte death remain incompletely defined. N6-methyladenosine (m6A), the most abundant internal modification of eukaryotic mRNA, is installed by the methyltransferase-like 3 (METTL3)-containing writer complex and regulates RNA fate. Here, we investigated whether METTL3-mediated m6A modification contributes to PANoptosis-like cardiomyocyte death during I/R injury. In mouse myocardial I/R and oxygen-glucose deprivation/reoxygenation (OGD/R) models, global m6A levels and METTL3 expression were markedly increased. Lactate accumulation was associated with p300-dependent H3K18 lactylation (H3K18la) enrichment at the Mettl3 promoter, suggesting a metabolic-epigenetic mechanism for METTL3 transcriptional upregulation. Functionally, METTL3 promoted PANoptosis-related death signaling, strengthened the association of ZBP1 with PANoptosis-related components, and aggravated infarction, adverse remodeling, and cardiac dysfunction, whereas METTL3 deletion or pharmacological inhibition with STM2457 was protective. Mechanistically, METTL3 enhanced m6A modification of Egr1 mRNA, thereby increasing EGR1 expression through YTHDF1-mediated translational regulation and IGF2BP2-mediated mRNA stabilization. EGR1 further activated Zbp1 transcription, and EGR1 restoration partially reversed the protective effects of METTL3 deficiency. These findings identify a lactate-H3K18la-METTL3-EGR1-ZBP1 axis that drives PANoptosis-like cardiomyocyte death and suggest METTL3 inhibition as a potential strategy against I/R-induced cardiac injury.
    Keywords:  N6‐methyladenosine; PANoptosis; methyltransferase‐like 3; myocardial ischemia‐reperfusion injury
    DOI:  https://doi.org/10.1002/mco2.70962
  48. Nat Commun. 2026 Sep 23. pii: 9450. [Epub ahead of print]17(1):
    Structural basis of step II spliced leader RNA trans-splicing in trypanosomatid parasites.
    Théo Nadenoen, Franco Agustín Biglione, Marylène Vandevenne, Arnaud Vanden Broeck.
      Messenger RNA (mRNA) synthesis is fundamental to eukaryotic gene expression. In kinetoplastid parasites, including the human pathogens Trypanosoma and Leishmania, mRNAs are produced through a mechanism called Spliced Leader (SL) RNA trans-splicing. In this process, a short SL exon from a small noncoding RNA is joined to the 5' end of every mRNA, ensuring transcript stability and translation. Despite decades of study, the structural and mechanistic basis of SL trans-splicing remains elusive. Here, we report cryogenic electron microscopy structures of step II SL trans-splicing machineries from Leishmania tarentolae. These structures reveal the molecular mechanism of SL exon ligation and uncover lineage-specific adaptations that remodel the trypanosomatid trans-spliceosome for SL trans-splicing while preserving fundamental spliceosomal chemistry. Altogether, our results establish a mechanistic framework for SL trans-splicing and illuminate the evolutionary diversification of RNA processing in deeply diverged eukaryotes.
    DOI:  https://doi.org/10.1038/s41467-026-77480-6
  49. Mol Plant Pathol. 2026 Sep;27(9): e70352
    The Histone Demethylase JMJD2-Dependent Regulation of rDNA Transcription and Integrity of Nucleolus Is Required for Fungal Development and Pathogenicity in the Rice Blast Fungus.
    Song Hee Lee, Taehyeon Kim, Joo Hyun Lee, Jiyeun Park, Ki-Tae Kim, Hokyoung Son, Junhyun Jeon.
      The nucleolus is a central hub for nuclear functions, including, but not limited to, ribosome biogenesis in mammals and budding yeast. However, how the nucleolus is regulated and contributes to fungal development and pathogenesis is poorly understood. Here we report that a JmjC domain-containing histone demethylase MoJMJD2 is required for rDNA transcription and nucleolar integrity in the rice blast fungus, Magnaporthe oryzae. MoJMJD2 generates two alternatively spliced isoforms with distinct subcellular localization patterns, suggesting coordinated roles in gene regulation in the nucleolus and nucleoplasm. Deletion of MoJMJD2 rendered the fungus defective in hyphal growth, sporulation and pathogenicity. Notably, loss of MoJMJD2 led to mislocalization of a nucleolar protein to the nucleoplasm and a dramatic reduction of cellular protein synthesis, suggesting the disruption of functional nucleolar structure. Taken together, these results indicate that nucleolar integrity and functions, which are under epigenetic control associated with MoJMJD2, are required for the development and pathogenicity of the rice blast fungus.
    Keywords:   Magnaporthe oryzae ; alternative splicing; epigenetic regulation; histone demethylase; nucleolus; rDNA transcription
    DOI:  https://doi.org/10.1111/mpp.70352
  50. Trends Mol Med. 2026 Sep 21. pii: S1471-4914(26)00217-0. [Epub ahead of print]
    The splicing axis of aging: mechanisms and therapeutic opportunities.
    Sada Raza, Ankita Kumari, Maciej Cieśla.
      Aging is characterized by progressive loss of molecular fidelity that compromises stem-cell function and tissue homeostasis. Aging transcriptomes show widespread disruption of RNA processing, including increased intron retention, cryptic splice-site usage, and altered RNA quality control. These changes arise from somatic mutations as well as accumulated transcriptional, metabolic, and proteostatic stress. Importantly, similar splicing abnormalities are observed in age-associated diseases such as clonal hematopoiesis and neurodegeneration, overlapping with physiological aging states. Here, we synthesize mechanistic, stem-cell, and longevity studies to define declining RNA-processing fidelity as a unifying contributor to aging across systems. We propose the 'splicing axis of aging' as a framework linking RNA-processing dysfunction to tissue decline and outline emerging therapeutic strategies to restore spliceosome integrity and RNA homeostasis.
    Keywords:  clonal hematopoiesis; gene expression; neurodegeneration; spliceosome; splicing; tissue aging
    DOI:  https://doi.org/10.1016/j.molmed.2026.09.001
  51. NAR Cancer. 2026 Sep;8(3): zcag025
    IGF2BP3 remodels RISC occupancy to control microRNA targeting in leukemia.
    Lyna E S Kabbani, Shruti Kapoor, Gunjan Sharma, Martin Gutierrez, Zachary T Neeb, Amit K Jaiswal, Alexander J Ritter, Sol Katzman, Jordyn E Feldman, Dinesh S Rao, Jeremy R Sanford.
      IGF2BP3 is an oncofetal RNA-binding protein that promotes leukemogenesis, but the mechanisms by which it remodels post-transcriptional gene regulation remain incompletely understood. Because IGF2BP3 binds extensively within 3' untranslated regions and has been implicated in microRNA (miRNA)-mediated regulation, we asked whether IGF2BP3 controls access of the RNA-induced silencing complex (RISC) to endogenous messenger RNA (mRNA) targets in leukemia cells. Using AGO2 miR-eCLIP in control and IGF2BP3-deficient MLL-AF4 B-lymphoblastic leukemia cells, we found that loss of IGF2BP3 broadly redistributes AGO2 occupancy toward 3' UTRs of IGF2BP3-bound transcripts. AGO2 gains were enriched near miRNA target sites and on transcripts associated with proliferative and oncogenic pathways. Chimeric AGO2-miRNA reads revealed transcript- and miRNA-specific remodeling of RISC interactions, with enhanced miR-181 occupancy on oncogenic transcripts following IGF2BP3 loss. Functionally, miR-181a overexpression impaired leukemic cell growth, partially phenocopying IGF2BP3 deletion. Motif analyses indicated that IGF2BP3 and AGO2 converge on related 3' UTR sequence environments, while biochemical competition assays demonstrated that purified IGF2BP3 can displace AGO2-containing RISC complexes from a shared RNA substrate. Together, these findings support a model in which IGF2BP3 restricts RISC access to select 3' UTR regulatory elements, thereby reshaping miRNA-target interactions and sustaining leukemic gene expression programs. Rather than acting solely as an mRNA stabilizing factor, IGF2BP3 functions as a transcript-selective regulator of RISC accessibility in leukemia.
    DOI:  https://doi.org/10.1093/narcan/zcag025
  52. Int J Mol Sci. 2026 Sep 18. pii: 8318. [Epub ahead of print]27(18):
    A Pilot Proteomics Analysis of Mycobacterium tuberculosis Lacking a Putative Short-Chain Dehydrogenase Rv0148.
    Gunapati Bhargavi, Anbarasu Deenadayalan, Kannan Palaniyandi, Selvakumar Subbian.
      Mycobacterium tuberculosis (Mtb) is an intracellular pathogen that survives in host cells by resisting hostile antimicrobial defenses. However, the molecules and mechanisms that contribute to Mtb's intracellular survival are not fully understood. We have previously reported that Rv0148, a putative short-chain dehydrogenase/reductase, plays a significant role in Mtb stress response and virulence in in vitro and in vivo models. To further understand the role of Rv0148 in regulating global functions of Mtb, we performed comparative pilot proteomic analysis between Δrv0148 mutant, and wild-type (WT) strains grown in axenic cultures. Mass spectrometry-based proteomics analysis identified 586 and 626 statistically significant differentially abundant proteins (SSDAP) in the WT and Δrv0148 mutant, respectively. Ontology analysis revealed that proteins involved in biological processes, including bacterial adaptation to host responses and protein homeostasis, were significantly more abundant, while peptidoglycan biosynthesis was less abundant in the mutant than the WT. Further network analysis revealed dysregulation of proteins involved in bacterial stress response, cell wall components, ribosomal and secretory proteins, suggesting impaired cell wall and translation machinery in Δrv0148. Functional categorization of differentially regulated proteins in Δrv0148 showed broad reprogramming in intermediary metabolism and stress adaptation. These findings suggest that Rv0148 may influence remodeling of cell wall components and bacterial physiology, potentially balancing Mtb survival and stress adaptation.
    Keywords:  LC/MS analysis; STRING analysis; capsule; cell wall; immune response; metabolism; mycobacterium; peptidoglycan; protein–protein interactions; stress adaptation
    DOI:  https://doi.org/10.3390/ijms27188318
  53. Expert Opin Drug Discov. 2026 Sep 22. 1-19
    The rapid emergence of small molecule RNA modulator hit discovery: unlocking the potential.
    Rachel Moore, Alessandro Bonetti, Rhona J Cox, Stefan Geschwindner, Mariacarmela Giurrandino, Sergio Martinez Cuesta, Stefan Schiesser.
       INTRODUCTION: RNA is now recognized as an active regulatory target rather than a passive intermediary, expanding therapeutic opportunities beyond protein-centric drug discovery. Small-molecule RNA modulators offer access to novel target space and new mechanisms to modulate protein targets that are difficult to drug directly, but clinical translation remains limited.
    AREAS COVERED: This review examines the principal challenges and opportunities in small-molecule RNA-targeted hit discovery: target prioritization based on genetics, structure, and function; mechanisms of modulation beyond splicing, including translation interference and targeted RNA degradation; the persistent gap between RNA structural engagement and functional outcome; hit-finding strategies; and hit-to-lead optimization. Here, the authors discuss how limitations do not lie solely in identifying RNA binders, but in predicting prospectively whether binding to a defined RNA structure will produce a functional consequence.
    EXPERT OPINION: Progress requires closing the structure-function-druggability loop through in-cell validation and RNA-specific druggability models, deploying targeted RNA degradation to convert silent binders into functional molecules, establishing standardized validation cascades and translational PK/PD frameworks, building RNA-native chemical infrastructure, and training AI on RNA-specific datasets. Pre-competitive infrastructure to generate shared structural and functional data will accelerate the field.
    Keywords:  Hit-to-lead optimization; RNA structure; RNA-targeting small molecules; artificial intelligence; druggable RNA; hit identification; target selectivity; targeted RNA degradation
    DOI:  https://doi.org/10.1080/17460441.2026.2736534
  54. Med Oncol. 2026 Sep 25. pii: 295. [Epub ahead of print]43(11):
    METTL16 promotes colorectal cancer progression and CD8+ T cell function through BCAT1-dependent branched-chain amino acid metabolism.
    Yanyan Hu, Shengying Li, Minjing Zhu, Xuedan Lin, Chaoju Gong, Zejun Fang.
      This study aims to investigate whether Methyl-Transferase-Like Protein 16 (METTL16) promotes colorectal cancer (CRC) progression through regulating branched-chain amino acid (BCAA) transaminase 1 (BCAT1)-mediated metabolism to modulate CD8+T cell-mediated anti-tumor immunity. METTL16 levels were measured in clinical CRC samples and cell models using IHC, qPCR and western blot. Functional assays (CCK-8, EdU, wound healing, transwell) were performed to evaluate the impact of METTL16 knockdown on CRC cell behaviors. A co-culture system with CD8+T cells was established to assess immune evasion mechanisms. RIP, MeRIP, and mRNA stability assays were conducted to explore METTL16's regulation of BCAT1 via m6A modification. Metabolomics analysis using LC-MS/MS quantified branched-chain amino acids (BCAAs). In vivo experiments utilized a xenograft mouse model to validate findings. METTL16 was elevated in CRC. Knockdown of METTL16 suppressed malignant phenotype of CRC cell, while enhancing CD8+T cell proliferation and cytotoxic molecule secretion (IFN-γ, IL-2, and GzmB). METTL16 regulated BCAT1 expression through m6A-dependent mRNA stabilization, promoting BCAAs metabolism. Rescue experiments demonstrated that BCAT1 overexpression reversed the regulation of METTL16 knockdown on tumor cell malignancy and CD8+ T cell responses. In vivo, METTL16 depletion inhibited tumor growth, reduced Ki-67 expression, and enhanced CD8+T cell infiltration and effector molecule levels. METTL16 drives CRC progression by promoting BCAT1-mediated BCAAs metabolism and facilitating immune evasion through suppression of CD8+T cell function.
    Keywords:  BCAT1; Branched chain amino acid metabolism; CD8+T cells; Colorectal cancer; METTL16
    DOI:  https://doi.org/10.1007/s12032-026-03410-7
  55. Biomed Pharmacother. 2026 Sep 22. pii: S0753-3322(26)00981-9. [Epub ahead of print]204 119945
    Acteoside alleviates Parkinson's disease-associated neurodegeneration and oxidative stress via an m6A-dependent Nrf2 regulatory axis.
    Yatan Li, Yujie Zeng, Qin Luo, Borui Zhang, Boyuan Ma, Xinling Yang, Ziyi Wang.
      Parkinson's disease (PD) is a major neurodegenerative disorder. However, current therapeutic strategies do not provide prevention or recovery of neuronal damage. Risk factors, including aging, exogenous toxins, and genetic factors, are strongly related to the development and prognosis of PD. Emerging evidence demonstrates that N6-methyladenosine (m6A) contributes to neurodegeneration in PD. In our study, we found the dysregulation of m6A in PD patients and mouse models, which disrupts the antioxidant mechanism, particularly the expression of Nrf2. In the current study, acteoside (ACT), a compound extracted from Cistanche tubulosa, was found to exert neuroprotective effects in dopaminergic neurons and improved the synucleinopathy in a mouse PD model. ACT significantly improved mitochondria function and alleviated oxidative stress in the PD mice. Moreover, the dysregulated m6A modification was improved by treatment of ACT. ACT treatment was associated with restored METTL3/FTO balance and increased m6A modification of Nrf2 mRNA with elevated Nrf2 mRNA stability and expression. These results provided evidence that ACT could be a potential therapeutic agent for PD.
    Keywords:  Acteoside; Cistanche tubulosa; N6-methyladenosine; Nrf2; Oxidative stress; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.biopha.2026.119945
  56. bioRxiv. 2026 Sep 18. pii: 2026.09.17.752471. [Epub ahead of print]
    A jumbo cyanophage encodes the most complete ribosomal protein set in the known virosphere.
    Isaac Meza-Padilla, Sarit Avrani, Kirsten M Müller, Jozef I Nissimov.
      Viruses encode ribosomal proteins (RPs), but their genomes usually harbor a single RP-coding gene. Here, we reannotate the genome of the jumbo cyanophage PhiMa05 and show that it encodes six RPs, an RP acetyltransferase, and a ribosome biogenesis protein. Evolutionary analyses suggest that these viral RP-coding genes may have been horizontally transferred to certain members of the Vampirovibrionia, a non-photosynthetic basal lineage of Cyanobacteriota, via integration of the viral genome.
    DOI:  https://doi.org/10.64898/2026.09.17.752471
  57. J Microbiol Biotechnol. 2026 May 07. 36 e2508039
    A Novel Translational Reprogramming of the Insertion Sequence IS1239 by 1-bp Deletion Resulted in Polymorphism of C-Terminal Amino Acid Sequences in the Pathogenic Bacterium Streptococcus pyogenes.
    Yun-Juan Bao, Zhong Liang, Zhi-Song Chen, Francis J Castellino.
      The insertion sequence family IS1239 has been found to mediate multiple asymmetric rearrangements in the pathogenic bacterium, Group A Streptococcus pyogenes (GAS), but not symmetric rearrangements as observed commonly in other bacteria. Sequence characterizations showed that the copies of IS1239 in GAS encode variable C-termini by utilizing flanking sequences downstream the insertion sites. We found that the variability of the C-termini was caused by translational reprogramming from a 1-bp frame-shift deletion at the 3'-terminus of the gene. The translational reprogramming results in extension and polymorphism of the C-terminal sequences, which was only observed in GAS. Selection analyses indicated that the C-terminal region of IS1239 proteins in GAS is under relaxed selection constraints, thus allowing more sequence changes in this region without affecting the transposition activity of this enzyme. We also showed that the insertion of IS1239 and the formation of flexible C-termini exhibit signatures related to evolutionary selection based on three lines of evidence: (i) copies of IS1239 in GAS were inserted in conserved genomic regions compared to those from Streptococcus pneumoniae; (ii) copies of IS1239 in GAS are more frequently inserted in the neighboring regions of tRNAs, rRNAs, or ribosomal proteins, but rarely interrupt their normal coding; (iii) the sites predicted to be under relaxed selective constraints in GAS lineage are enriched in regions outside the functional domains and near the 1-bp deletion which induced the polymorphism of C-termini of IS1239 in GAS.
    Keywords:  Evolutionary selection; Insertion sequences; Mobile elements; Streptococcus pyogenes
    DOI:  https://doi.org/10.4014/jmb.2508.08039
  58. Microbiol Spectr. 2026 Sep 21. e0010426
    Stress-dependent ribosome-associated proteomics reveals a role for Sis1 in thermotolerance and virulence in Cryptococcus neoformans.
    Maia F Mazzaferro, Alexandra C Benedetto, Amanda L M Bloom, Prabhakar Singh, Shichen Shen, Jun Qu, John C Panepinto.
      During human infection, Cryptococcus neoformans can disseminate to the central nervous system, causing often-fatal cryptococcal meningitis in individuals with compromised immunity. To acutely adapt to host micro-environments, C. neoformans employs mechanisms to reprogram its translatome to provide cells with tools to survive the stressors of the human host. The identities and functions of ribosome-associated factors that may modulate this process in C. neoformans remain unknown. We hypothesized that following host-related stressors, specific proteins associate with ribosomes and influence stress adaptation in C. neoformans. Utilizing a proteomic approach, termed RiboPROT, we analyzed the protein composition of mRNA-associated ribosomes from cells grown under unstressed (30°C), thermally stressed (shifted to 37°C), and oxidatively stressed (shifted to 2 mM H2O2) conditions. We identified unique factors enriched with actively translating ribosomes during host-related stressors. Phenotypic analysis of deletion mutants in selected ribosome-associated factors revealed that the J-domain protein Sis1 is important for growth at elevated temperature, Hsp70 and Hsp90 function, and virulence. The sis1Δ mutant also exhibited sensitivity to multiple drugs that cause mitochondrial perturbation, and growth on acetate as a sole carbon source suppressed the thermal growth defect at 38°C, suggesting that Sis1 supports mitochondrial homeostasis during thermal stress. Additionally, the sis1Δ mutant displayed transient hyper-repression of translation initiation during a shift to acute thermal stress at human body temperature but not at human febrile temperature. Global features of stress-responsive translatome reprogramming remained intact in the absence of Sis1, suggesting its role in thermotolerance and virulence is likely linked to regulation of specific targets involved in mitochondrial homeostasis in C. neoformans.IMPORTANCEFungal pathogens are an underrepresented and emerging global public health threat. In 2022, the World Health Organization recognized Cryptococcus neoformans as the top fungal high-priority pathogen, signifying the urgency for increased research and new therapeutics. The mechanisms by which C. neoformans adapts to the insults of the human body and causes systemic disease remain incompletely understood. Although the ribosome is essential to fungal viability and is targetable by small molecules, the conservation of the eukaryotic ribosome hampers the development of molecules that are selective for the fungal ribosome. Here, we identify stress-dependent ribosome-associated factors in C. neoformans and highlight one identified protein, Sis1, demonstrating its contribution to thermotolerance and virulence. Identification of stress-induced ribosome-associated factors and uncovering their biological role in the cell may identify pathways for selective therapeutic targeting of the fungal ribosome.
    Keywords:  Cryptococcus; Sis1; heat shock proteins; ribosome remodeling; stress-responsive translation
    DOI:  https://doi.org/10.1128/spectrum.00104-26
  59. J Trace Elem Med Biol. 2026 Sep 19. pii: S0946-672X(26)00147-1. [Epub ahead of print]98 127961
    Mechanistic Insight into the Role of Maresin-1 in Attenuating Lithium-Induced Nephrogenic Diabetes Insipidus in Rats via Regulation of cAMP/AQP2 Signaling and SERCA2b Dependant Endoplasmic Reticulum Stress.
    Sarah Ragab Abd El-Khalik, Norhan Ahmed AbuoHashish, Haidy Abdelaziz Khattab, Elham Nasif, Amal Mohamed Abdelsattar, Hanem Mohamed Rabah.
       BACKGROUND: Nephrogenic diabetes insipidus (NDI), one of the common complications of chronic administration of lithium, is characterized by severe urine concentrating defects. It is associated with aberrant regulation of aquaporin-2 (AQP2) proteins as well as endoplasmic reticulum (ER) stress. Therefore, we evaluated renoprotective effects of Maresin-1 (MaR-1) and its associated molecular mechanisms in Li-induced NDI.
    METHODS: forty-eight adult male Wistar albino rats were randomly distributed into four equal groups: control, MaR-1 control (40 ug/kg/day intraperitoneally), NDI (LiCl; 40 mmol/kg dry food), and NDI + MaR-1 groups for 14 days. Renal function status was assayed in blood and urine. The gene expression of AQP2 and SERCA2b in renal tissue homogenates was assessed by qRT- PCR. Biochemical analyses of autophagy and ER stress markers as well as cAMP levels were detected. Also, histopathological analysis was determined.
    RESULTS: Administration of MaR-1 significantly improved polyuria and urine osmolality which are attributed to marked elevation of cAMP level and upregulated AQP2 expression. Furthermore, MaR-1 significantly increased SERCA2b expression leading to attenuated ER stress (GRP78 and CHOP) and decreased autophagy markers (beclin-1 and LC3BII).
    CONCLUSION: MaR-1 exhibits a novel therapeutic approach for attenuation of Li-induced NDI via regulation of cAMP/AQP2 signaling and modulation of SERCA2b dependent ER stress.
    Keywords:  Aquaporin-2; ER stress; Lithium; Maresin-1; Sarco-endoplasmic reticulum calcium ATPase
    DOI:  https://doi.org/10.1016/j.jtemb.2026.127961
  60. Cancer Metastasis Rev. 2026 Sep 23. pii: 71. [Epub ahead of print]45(4):
    Extracellular vesicles shape tumourigenesis: from signalling networks to systemic progression.
    Stephanie B Telerman, Janusz Rak, Adam Telerman.
      Extracellular vesicles (EVs) are established mediators of long-range intercellular communication in cancer, transferring oncogenic and regulatory cargo that reshapes recipient cells across tissues. Recent integrative multi-omics analyses of small EVs (sEVs) from healthy human donors consistently identify TSAP6/STEAP3 among the most abundant and reproducible sEV components, providing a physiological context for its role in sEV biology. Rather than acting solely as a downstream effector of p53, TSAP6 functions within a broader regulatory network by associating with TPT1/TCTP, which engages DDX3 and promotes the incorporation of RNAs, including microRNAs, into sEVs. The resulting p53-TSAP6-TCTP-DDX3 axis constitutes a wide-reaching regulatory system with non-cell-autonomous impact on cellular communication. Notably, TCTP sustains sEV-mediated signalling even in p53-mutant contexts. We suggest that these findings are consistent with other advances in cancer linking oncogenic transformation with EV biology. Together, these observations support regulated EV-mediated information transfer as a mechanism contributing to cancer progression and systemic cellular reprogramming. Conversely, reduction in EV abundance, altered cargo content, or signalling capacity may contribute to the activation of the tumour reversion programme in TCTP-dependent experimental models.
    Keywords:  DDX3; Intercellular communication; Small extracellular vesicles; TCTP; TSAP6/STEAP3; Tumour reprogramming/reversion
    DOI:  https://doi.org/10.1007/s10555-026-10377-4
  61. Cell Biochem Biophys. 2026 Sep 23.
    Itaconation and Succination as Metabolite-Derived Cysteine Modifications in Inflammatory Signalling: Biochemical Mechanisms, Chemoproteomic Mapping, and Therapeutic Opportunities.
    Asif Ahmad Bhat, Shivkanya Fuloria, Riya Thapa, Nina Varghese, Rohini Karunakaran, Sumita Bhatia, Kamal Narain, Anupam Biswas, Sangita Biswas, Neeraj Kumar Fuloria.
      Inflammatory activation rewires cellular metabolism and generates electrophilic metabolites that can modify reactive cysteine residues. This review focuses on two metabolite-derived cysteine modifications: itaconation, driven by aconitate decarboxylase 1 (ACOD1)-dependent itaconate production, and succination, driven by fumarate accumulation. Although both involve cysteine engagement, they differ in chemical stability, metabolite source, cellular distribution, glutathione competition, and functional outcome. Itaconation is linked to Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid 2-related factor 2 (NRF2) signalling, glycolytic control, kinase regulation, innate immune sensing, interferon responses, and inflammatory cell death, whereas succination is most strongly associated with stable S-(2-succino)cysteine (2SC) formation, fumarate excess, mitochondrial dysfunction, redox stress, inflammasome regulation, and pyroptosis. A central theme of this review is that endogenous itaconate and fumarate must be distinguished from electrophilic derivatives such as 4-octyl itaconate, dimethyl itaconate, and dimethyl fumarate, because these compounds differ in uptake, reactivity, target engagement, and pharmacological interpretation. We distinguish direct adduct mass spectrometry from competitive cysteine profiling and metabolite-mapping approaches, which can quantify bulk adduct burden, relative cysteine engagement, metabolite distribution, or compartment-specific cysteine state, but do not necessarily establish endogenous site occupancy. Proteomic and chemoproteomic approaches can prioritise metabolite-responsive cysteines, but functional relevance requires site-level validation, residue perturbation, and biochemical rescue. By comparing itaconation and succination across chemistry, target selection, inflammatory signalling, and therapeutic translation, this review defines the evidence needed to identify metabolite-sensitive cysteines as genuine regulatory nodes rather than detectable covalent adducts.
    Keywords:  Chemoproteomics; Cysteine Modification; Immunometabolism; Inflammatory Signalling; Itaconation; Succination
    DOI:  https://doi.org/10.1007/s12013-026-02184-z
  62. Poult Sci. 2026 Sep 14. pii: S0032-5791(26)01393-3. [Epub ahead of print]105(12): 107761
    Advances in RNA m6A modification research and its role in poultry economic traits.
    Jing Liu, Haodong Liu, Xuwen Huang, Zhixiang Xiao, Site Li, Xiaolong Hu, Sanfeng Liu, Huirong Mao, Biao Chen.
      N6-methyladenosine (m6A) is the most abundant and evolutionarily conserved internal epitranscriptomic modification on eukaryotic mRNA, playing pivotal roles in animal growth, development, metabolism, and immune responses by modulating mRNA splicing, stability, and translation efficiency. With advancements in technologies such as MeRIP-seq, GLORI-seq, and Nanopore direct RNA sequencing, researchers can now characterize the dynamic landscape of m6A modifications at the transcriptome-wide level. This review summarizes the fundamental features of m6A modifications, compares various detection methods and computational analytical approaches, and critically synthesizes recent progress on the roles of m6A modifications in poultry skeletal muscle development, adipose deposition, reproduction, and immunity and disease resistance. Particular emphasis is placed on the regulatory mechanisms of key enzymes, including METTL3/14, FTO, ALKBH5, and the YTHDF protein family. The potential applications, prospects and current limits of RNA m6A modification as a molecular breeding tool in poultry are also discussed.
    Keywords:  Detection methods; Differentially m6A-modified genes; Poultry economic traits; RNA m6A modification; m6A-modifying enzymes
    DOI:  https://doi.org/10.1016/j.psj.2026.107761
  63. iScience. 2026 Oct 16. 29(10): 116105
    Coordinated regulation of the metaboproteome by Hsp90 chaperones controls metabolic plasticity.
    R Felipe Perez, Gianna L Mochi, Julia K Burkacki, Victoria Zoccoli-Rodriguez, Landon D Arcadi, Sarah J Backe, Joel R Wilmore, Mark R Woodford.
      Heat shock protein 90 (Hsp90) chaperones participate in the stabilization and activation of hundreds of proteins, thereby acting as signaling hubs. A mitochondrial subpopulation of Hsp90 has been previously described; however, little is known about its role in metabolism. Here, we showed that loss of individual Hsp90 isoforms differentially affects oxygen consumption and metabolic flexibility. Proteomic and metabolomic evaluation demonstrated that Hsp90 regulates the mitochondrial metabolic network, including respiration, fatty acid oxidation, and redox homeostasis. Loss of the mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) induced compensatory binding of Hsp90s to TRAP1-dependent proteins, indicating a mechanism for the role of Hsp90 chaperones in metabolic reprogramming. When considered with previous findings, a temporal pattern of regulation emerges whereby Hsp90s control the transcription, translation, import, and assembly of mitochondrial protein complexes. Our findings expand the scope of Hsp90-regulated processes and potentially inform the effects of isoform-specific Hsp90 inhibitors on metabolic reprogramming in cancer and other diseases.
    Keywords:  Hsp90; TRAP1; metabolism; metaboproteome; mitochondria; molecular chaperone
    DOI:  https://doi.org/10.1016/j.isci.2026.116105
  64. Int J Mol Sci. 2026 Sep 15. pii: 8196. [Epub ahead of print]27(18):
    HMGB1 Post-Translational Modifications in Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma: Current Evidence, Emerging Mechanistic Concepts, and Unresolved Questions.
    Cho Yiu Lau, Khadija Shahed Khan, Dora Lai-Wan Kwong, Wei Dai, Ngar Woon Kam.
      Nasopharyngeal carcinoma (NPC) is a geographically distinct malignancy closely associated with Epstein-Barr virus (EBV) infection and characterized by extensive epigenetic reprogramming within a highly immunosuppressive tumor microenvironment (TME). High-mobility group box 1 (HMGB1), a multifunctional chromatin-binding protein that can also act as an extracellular damage-associated molecular pattern (DAMP), has emerged as an important regulator of genome organization, transcriptional control, cellular stress responses, and immune signaling. Increased HMGB1 expression has been reported in NPC and is associated with adverse clinicopathological features and poor patient outcomes. Emerging evidence suggests that the diverse biological functions of HMGB1 are influenced by post-translational modifications (PTMs), which affect its subcellular localization, molecular interactions, and extracellular signaling functions. Through these regulatory mechanisms, HMGB1 may transition from a nuclear chromatin-associated protein to an extracellular mediator of immune and inflammatory responses. PTMs including acetylation, phosphorylation, glycosylation, oxidation, methylation, and lactylation have been implicated in regulating HMGB1 trafficking and function, although the specific roles of many of these modifications in NPC remain incompletely characterized. In this review, we summarize current evidence regarding HMGB1 PTMs and discuss their potential implications for EBV-associated NPC, with emphasis on nuclear regulation, immune crosstalk, and therapeutic response. We explicitly distinguish findings directly demonstrated in NPC from mechanistic insights derived from other malignancies and related disease models, and identify areas where proposed mechanisms remain hypothesis-generating rather than experimentally validated in NPC. By integrating current evidence with emerging mechanistic concepts, we highlight key knowledge gaps, unresolved questions, and priorities for future research. A better understanding of PTM-dependent HMGB1 regulation may facilitate the development of novel biomarker and therapeutic strategies for EBV-associated NPC.
    Keywords:  EBV; HMGB1; immune regulation; nasopharyngeal carcinoma; post-translational modifications; therapeutics; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms27188196
  65. Biogerontology. 2026 Sep 25. pii: 165. [Epub ahead of print]27(5):
    Turnera diffusa polysaccharides promote healthy aging through conserved stress response regulation and metabolic remodeling across multiple aging models.
    Hailing Wang, Rui Wu, Xuemei Zhang, Xin Meng.
      Aging is a progressive decline in physiological functions and the capacity to maintain homeostasis, representing a major risk factor for numerous chronic diseases. Geroprotectors, defined as natural or synthetic compounds capable of improving healthspan and delaying age-associated functional decline, have attracted increasing attention in aging research. However, clinically validated interventions for promoting healthy aging remain unavailable. Plant-derived polysaccharides, owing to their excellent safety profiles and diverse biological activities, have emerged as promising candidates for geroprotection. Turnera diffusa Willd. Ex Schult. (T. diffusa) has been reported to exhibit neuroprotective and reproductive system modulating properties; however, the geroprotective potential of its polysaccharides remains unexplored. In the present study, T. diffusa polysaccharides (TDP) were found to significantly extend lifespan and alleviate multiple age-associated physiological declines in both C. elegans and D. melanogaster models. Mechanistic investigations revealed that TDP enhanced the activation of conserved DAF-16/FOXO and HSF-1-mediated stress response pathways, thereby promoting antioxidant defense and maintaining proteostasis. Furthermore, 1H-NMR-based metabolomic analysis demonstrated that TDP partially restored age-related metabolic disturbances, particularly those associated with amino acid, energy, and lipid metabolism. These findings provide novel insights into the geroprotective potential of TDP and support its further investigation as a potential geroprotective candidate.
    Keywords:   Turnera diffusa polysaccharides; DAF-16/FOXO signaling pathway; Geroprotector effect; HSF-1 signaling pathway; Metabolomics, Hormesis
    DOI:  https://doi.org/10.1007/s10522-026-10514-0
  66. Biogerontology. 2026 Sep 19. pii: 161. [Epub ahead of print]27(5):
    Aging-modulatory effects of Pausinystalia macroceras (K. Schum.) Pierre polysaccharides are associated with DAF-16/FOXO and SKN-1/Nrf2 signaling in multiple aging models.
    Ahequeli Gemingnuer, Xuemei Zhang, Rui Wu, Xin Meng.
      With the global aging population and increasing burden of age-related diseases, delaying aging and maintaining healthspan have become important research priorities. Aging is a complex biological process involving progressive declines in physiological function, stress resistance, proteostasis, and metabolic homeostasis, driving the development of aging modulators that target conserved longevity-associated pathways. Although pharmacological and natural aging modulators have attracted growing attention, concerns regarding the long-term safety and clinical applicability of pharmacological interventions, together with the incompletely understood mechanisms of many natural modulators, remain. Plant-derived polysaccharides are promising natural aging modulators owing to their favorable biocompatibility, low toxicity, and diverse biological activities, but their aging-modulatory effects and underlying mechanisms remain insufficiently explored. In this study, Pausinystalia macroceras (K. Schum.) Pierre polysaccharides (PMP) were found to exhibit aging-modulatory effects in both Caenorhabditis elegans and Drosophila melanogaster aging models. PMP delayed the progression of aging by extending lifespan, preserving healthspan-associated functions, and maintaining physiological fitness without adversely affecting growth, feeding behavior, or reproductive capacity. PMP also enhanced resilience to diverse environmental stresses and attenuated age-associated physiological deterioration. At the cellular level, PMP maintained redox and proteostasis homeostasis by reducing intracellular reactive oxygen species accumulation, lipofuscin deposition, and polyglutamine aggregation. These protective effects were associated with enhanced DAF-16/FOXO- and SKN-1/Nrf2-mediated longevity and stress-response signaling, accompanied by increased downstream antioxidant defenses, including SOD-3 and GST-4. PMP further alleviated age-associated metabolic disturbances by modulating amino acid, carbohydrate, and energy metabolism, indicating its ability to preserve metabolic homeostasis during aging. Overall, PMP delays aging progression in association with coordinated regulation of longevity signaling, stress resistance, proteostasis, and metabolic homeostasis, providing a mechanistic basis for its development as a natural aging-modulatory agent.
    Keywords:   C. elegans ; D. melanogaster ; Pausinystalia macroceras (K. Schum.); Aging-modulatory; DAF-16/FOXO; Pierre polysaccharides; SKN-1/Nrf2, Hormesis, Hormetin
    DOI:  https://doi.org/10.1007/s10522-026-10509-x
  67. EMBO Rep. 2026 Sep 22.
    Nucleolar reorganization on stress depends on physicochemical changes due to reduced nascent rRNA synthesis.
    Sinjini Ghosh, Souvik Sen, Aprotim Mazumder.
      Successive maturation of ribosomal subunits occurs through multilayered phase-separated structures of the cell nucleolus. The spatio-functional relationship between transcription of rRNA and nucleolar substructures, and how this adapts to cellular stress remain incompletely understood. In this study, we resolve the sub nucleolar structures using expansion microscopy to reveal ordered structures of fibrillar center (FC) and dense fibrillar component (DFC) domains as nested shells, which are reorganized upon cellular stress like DNA damage or RNA polymerase I (RNAPI) inhibition. Direct visualization of nascent (5' ETS) and mature (28S or 18S) rRNA suggests that rRNA synthesis is a critical regulator of nucleolar size and organization. Nucleolar reorganization upon stress emerges to be a direct function of nascent rRNA levels. Stress-induced transcription inhibition can remodel the sub-nucleolar compartments to a low mobility state and perturbs the nucleolar pH gradient due to the missing rRNA scaffold and other factors. We show that rather than signaling to mediate rDNA repair, nucleolar reorganization arises naturally from reduced rRNA levels and the resultant biophysical restructuring of the nucleolus under cellular stress.
    DOI:  https://doi.org/10.1038/s44319-026-00932-z
  68. Plant Cell Rep. 2026 Sep 25. pii: 305. [Epub ahead of print]45(10):
    Alternative splicing-dependent T218 phosphoregulation controls SR45.1 nuclear organization and salt stress responses in Arabidopsis.
    Mohammed Albaqami.
       KEY MESSAGE: Alternative splicing creates an SR45.1-specifi c phosphoregulatory region in which threonine 218 (T218) contributesto nuclear speckle organization, RNA regulatory responses, and salt tolerance in Arabidopsis. Alternative splicing expands protein and functional diversity in plants, yet the mechanistic basis by which closely related splice isoforms acquire distinct biological functions remains poorly understood. In our previous work, we showed that AS of the Arabidopsis splicing factor SR45 generates two isoforms with contrasting roles in salt stress response, where SR45.1, but not SR45.2, restores salt tolerance in the sr45 mutant background. The molecular basis underlying this isoform-specific functional divergence remained unclear. Here, we investigated the role of two conserved phosphosites, threonine 218 (T218) and serine 219 (S219), within the unique C-terminal region of SR45.1, a sequence absent from SR45.2. Site-directed mutagenesis was used to generate phospho-disruptive SR45.1 variants, which were then expressed in the sr45 mutant background. Functional analyses revealed that substitution of T218, but not S219, abolished the salt-tolerance function of SR45.1. Mechanistically, disruption of T218 altered SR45.1 nuclear speckle organization, resulting in fewer enlarged nuclear speckles compared with the numerous small speckles observed in functional lines. T218 disruption was further associated with altered AS of stress-related targets, including SOS4 and RD20, as well as reduced transcript accumulation of salt-responsive genes, including RD29A, RD29B, ADH1, and DREB2A. Together, our findings identify T218 phosphoregulation as a critical determinant of SR45.1 function, linking AS-generated isoform diversity to post-translational regulation, nuclear organization, and plant salt stress responses.
    Keywords:  Abiotic stress; Nuclear speckles; Protein phosphorylation; RNA processing; Serine/arginine-rich protein
    DOI:  https://doi.org/10.1007/s00299-026-03999-z
  69. Int J Mol Sci. 2026 Sep 13. pii: 8148. [Epub ahead of print]27(18):
    Alterations of Gene Expression and Signaling Pathway Activity in Venous Smooth Muscle Cells After Uremic Serum Exposure.
    Youyou Zheng, Unimunkh Uriyanghai, Christine Wai, Mihaela Mocanu, John S Poulton, Prabir Roy-Chaudhury, Gang Xi.
      Uremia is the most common pathophysiological symptom in chronic kidney disease (CKD) patients, particularly in end-stage kidney disease (ESKD) patients. Uremia can lead to several vein-specific vascular diseases, such as renal vein thrombosis (RVT), deep vein thrombosis (DVT) and dialysis access-induced venous stenosis. One of our previous studies demonstrated that uremic serum exposure induced different cellular responses in pig venous smooth muscle cells (vSMCs) compared with arterial smooth muscle cells (aSMCs). To explore the underlying mechanisms responsible for vein-specific cellular responses, bulk RNA sequencing was utilized to examine differential gene expression in porcine vSMCs after uremic serum exposure. Differentially expressed genes (DEG) analysis revealed that 408 genes were upregulated, and 387 genes were downregulated after uremic serum treatment. Gene Ontology Biological Process analysis demonstrated that uremic serum exposure led to transcriptomic downregulation of cellular energy expenditure activities, such as the Cell Cycle, and positive transcriptomic enrichment of Cellular Response to Endoplasmic Reticulum (ER) stress, unfolded protein response and hypoxia. Both Gene Set Enrichment Analysis (GSEA) and Overrepresentation Analysis (ORA) obtained similar results. ORA revealed additional signaling pathways predicted to be transcriptomically downregulated, such as the Hippo signaling pathway and Focal Adhesion and Cytoskeletal Structure Regulating pathways. ORA also predicted several positively enriched signaling pathways related to cellular stress responses and waste disposal. To precisely identify vSMCs-specific alterations, an interaction-based KEGG GSEA was performed. The analysis revealed several significantly different responses between vSMCs and aSMCs, such as Protein Processing in the Endoplasmic Reticulum, Integrated Stress Response signaling pathway and Mitophagy, which showed more positive responses in vSMCs, while Oxidative Phosphorylation showed a more positive response in aSMCs. These altered signaling pathways may be responsible for vein-specific clinical symptoms, such as venous segment stenosis in arteriovenous fistula, observed in CKD/ESKD patients.
    Keywords:  bulk RNA sequencing; uremia; venous smooth muscle cells; venous stenosis; venous thrombosis
    DOI:  https://doi.org/10.3390/ijms27188148
  70. Cells. 2026 Sep 17. pii: 1683. [Epub ahead of print]15(18):
    Mitochondrial Modulation as a Therapeutic Entry Point in Neurodegeneration.
    Mateusz Mamala, Izabela Skowron, Karolina Marczuk, Arkadiusz Bujas, Jolanta Harasiuk, Julita Kulbacka.
      Mitochondrial dysfunction is a recurrent but context-dependent feature of neurodegenerative disease, and its position in the pathogenic cascade differs fundamentally between disorders. This narrative review argues that this heterogeneity, rather than mitochondrial biology itself, determines therapeutic tractability. We synthesize evidence on mitochondrial regulation of neuronal development, organelle quality control, redox signaling and neuroinflammation; on oxidative biomarkers, whose clinical use remains constrained by limited disease specificity, methodological heterogeneity and insufficient longitudinal validation; and on therapeutic strategies ranging from antioxidants and NAD+ augmentation to mitochondrial genome engineering, targeted delivery and organelle transfer. A consistent pattern emerges across these domains: broadly acting interventions have repeatedly failed in sporadic disease, whereas the strongest translational signals arise where mitochondrial dysfunction is genetically anchored and pathway-proximal. Mitochondrial modulation is therefore unlikely to provide a universal disease-modifying strategy, but remains a useful, carefully targeted addition for patient groups identified by genetic or specific biological markers.
    Keywords:  mitochondrial DNA; mitochondrial dysfunction; mitochondrial therapeutics; mitophagy; neurodegeneration; oxidative stress; redox biomarkers
    DOI:  https://doi.org/10.3390/cells15181683
  71. Aging (Albany NY). 2026 Sep 19. 18(1): 1280-1315
    mTOR signaling in aging: from causality to geroprotective interventions and hallmark-level outcomes.
    Natalia Bobok.
      The mechanistic target of rapamycin (mTOR) pathway is an important integrator of processes involved in aging and longevity, coordinating nutrient sensing, metabolic adaptation, and cellular stress responses. This review presents a three-section framework in which mTOR functions as a dynamic signaling hub coordinating multiple biological processes underlying the aging process. Evidence from genetic, experimental, and translational studies supports a causal role for mTOR signaling in lifespan regulation in model organisms, whereas human data remain predominantly associative but biologically consistent. mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) regulate distinct yet complementary aspects of cellular metabolism, proteostasis, autophagy, stress adaptation, and tissue homeostasis. Major geroprotective interventions-including autophagy activation, dietary interventions, physical activity, and senotherapeutics-partly converge on mTOR signaling but also engage parallel pathways. This adaptive regulation restores anabolic-catabolic balance, enhances stress resilience, and improves metabolic flexibility. Collectively, the available evidence identifies mTOR as an important integrative node linking multiple hallmarks of aging and diverse geroprotective interventions. Rather than representing a single therapeutic target, mTOR should be viewed as a context-dependent signaling hub which precise, tissue-specific modulation may promote healthy aging and support future geroscience-based interventions.
    Keywords:  geroprotective interventions; hallmarks of aging; mTOR signaling; mTORC1; mTORC2
    DOI:  https://doi.org/10.18632/aging.206423
  72. J Cardiovasc Dev Dis. 2026 Sep 03. pii: 435. [Epub ahead of print]13(9):
    Atherosclerotic Cell Fates: A Single-Cell View of ER Stress.
    Shuyi Li, Xiang Lu.
      The role of endoplasmic reticulum (ER) stress in atherosclerosis has long been recognized, but whether it acts as a uniform pathological signal across all cell types has remained unclear. With the advancement of single-cell sequencing technology (scRNA-seq), we can analyze this problem at the resolution of a single cell subpopulation. In this review, we have synthesized the recent evidence from single-cell studies and proposed the "cell type-specific differential response" mode. We believe that endoplasmic reticulum stress does not universally have a pro-atherosclerotic effect. On the contrary, it shows a differential pattern in different atherosclerotic-related cell subpopulations. For example, endoplasmic reticulum stress is activated in monocytes but inhibited in certain macrophage subsets and endothelial cell subsets and dynamically regulated during phenotypic transitions in smooth muscle cells. We explored the underlying mechanisms of this heterogeneity, its impact on plaque progression, and the theoretical basis of subpopulation targeted treatment strategies. Ultimately, we concluded that recognizing the cellular heterogeneity of endoplasmic reticulum stress is the foundation for understanding and precisely intervening in atherosclerotic diseases.
    Keywords:  ER stress; atherosclerosis; macrophage; scRNA-seq
    DOI:  https://doi.org/10.3390/jcdd13090435
  73. Cells. 2026 Sep 15. pii: 1662. [Epub ahead of print]15(18):
    METTL3/IGF2BP1 Axis Orchestrates m6A-Dependent NCAM1 Preservation to Combat Age-Related Cognitive Decline.
    Guohua Ji, Yujie Zhao, Xu Liu, Xiaopeng Li, Liang Lu, Fengji Liang, Yanhong Yuan, Yuying Dai, Bo Li, Yanxiang Qu, Bo Song, Lina Qu.
      Age-related decline in learning and memory functions poses significant challenges in an aging society, with epigenetic dysregulation emerging as a key contributor to cognitive deterioration. As the most prevalent internal RNA modification, N6-methyladenosine (m6A) dynamically orchestrates neural transcriptome plasticity through its "writers," "erasers," and "readers," yet its role in aging-associated cognitive impairment remains underexplored. This study employs an integrated epitranscriptomic approach to investigate m6A-mediated regulation in hippocampal aging processes. Through comparative m6A-mRNA epitranscriptomic microarray analysis of senescence-accelerated mouse prone 8 (SAMP8) and senescence-resistant SAMR1 hippocampi, we identified neural cell adhesion molecule 1 (NCAM1) as a key m6A-regulated effector whose decreased expression correlates with accelerated cognitive deterioration. Mechanistically, we revealed that Methyltransferase-like 3 (METTL3)-mediated m6A modification governs Ncam1 mRNA stability through insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) reader protein-dependent mechanisms, forming a regulatory axis that modulates cyclic AMP response element-binding protein (CREB) signaling pathway activity. Remarkably, targeting of this METTL3/IGF2BP1/NCAM1 axis significantly attenuated cognitive deficits in aged SAMP8 mice. Our findings establish an m6A methylation-dependent paradigm for NCAM1-mediated cognitive preservation during aging, uncovering a novel epitranscriptomic layer in age-related neurodegeneration.
    Keywords:  METTL3; NCAM1; learning and memory; m6A; senescence
    DOI:  https://doi.org/10.3390/cells15181662
  74. Biomolecules. 2026 Sep 10. pii: 1313. [Epub ahead of print]16(9):
    Comparative Analysis of Reported Gene Targets and Binding Regions of Glu-CTC tRNA Fragments Across Human Diseases.
    Nikita Gulati, Andrey Grigoriev.
      Recurrent detection of overlapping tRNA-derived fragments (tRFs) across diverse disease conditions supports the emerging view that tRFs may act as regulatory molecules rather than random degradation products. While cases of identical tRFs have been described, their comparative analyses are lacking. tRF-Glu-CTC is one such fragment, repeatedly detected in various pathological conditions. We performed a comparative analysis of tRF-Glu-CTC isoforms, their targets and binding regions reported in 18 disease-associated studies. An 18-nucleotide sequence, TCCCTGGTGGTCTAGTGG, was identified in most (14 out of 18) of these studies despite differences in tRF naming, length and disease context. Several reported tRF targets showed consistent binding regions, with reverse complementarity to the tRF sequence. Comparison with databases of tRF targets, tatDB and tRFTar, identified matching target entries and sequence overlaps, often involving common regions rather than full-length matches. Exploratory analysis of target homologs further illustrated that related genes might share candidate target sites. Our findings indicate that tRF-Glu-CTC represents a recurrent candidate regulatory fragment potentially relevant in a broad range of human diseases. Its structural stability, extracellular vesicle association, detection in multiple species and a core sequence shared between related isoforms support further investigation of its biological and translational relevance. Our work illustrates how tRF target databases can be leveraged to advance smaller-scale tRF studies.
    Keywords:  gene regulation; tRF databases; tRF-Glu-CTC; tRNA-derived fragments; target recognition
    DOI:  https://doi.org/10.3390/biom16091313
  75. bioRxiv. 2026 Sep 22. pii: 2026.09.15.751695. [Epub ahead of print]
    Specific host translation perturbations promote Tn Smu 1 loss independently of the canonical ImmA regulator.
    Liang Bao, Todd Kitten, Ping Xu.
      Integrative and conjugative elements (ICEs) are major drivers of horizontal gene transfer and bacterial genome evolution. Although ICE-encoded regulatory circuits have been extensively characterized, the impact of host physiology on the stability of integrated ICEs remains poorly understood. Here, we identify a host-dependent pathway that links specific host translation perturbations to loss of the ICE Tn Smu1 in Streptococcus mutans . Analysis of host-gene deletion mutants revealed that disruption of fmt , rnjA , or rnjB -three translation-associated host genes-reproducibly promoted Tn Smu1 loss through a mechanism that bypasses the canonical ICE-encoded metalloprotease ImmA but remains dependent on the native attachment site attR . This phenotype was selective, as mutations affecting other essential cellular functions, including protein folding, tRNA modification, cell division, and fatty acid biosynthesis, failed to destabilize Tn Smu1 despite undergoing the same experimental evolution and accumulating adaptive genomic changes. Preventing Tn Smu1 loss in these translation-associated mutants markedly reduced bacterial growth, whereas loss of the element improved fitness, indicating that ICE elimination alleviates the cost associated with Tn Smu1 retention under these conditions. Finally, we show that the relationship between host translation and Tn Smu1 stability extends to a genetically distinct S. mutans clinical isolate, although with strain-dependent penetrance. Together, these findings identify host translational state as an important physiological determinant of Tn Smu1 stability and reveal that bacterial hosts can influence the maintenance of integrated mobile genetic elements through mechanisms that extend beyond element-encoded regulatory circuits.
    DOI:  https://doi.org/10.64898/2026.09.15.751695
  76. Synthesis (Stuttg). 2026 Feb;58(4): 344-354
    Biosynthesis and Synthesis of Griseoviridin and Viridogrisein.
    Leyan Xu, Hans Renata.
      Griseoviridin and viridogrisein are synergistic type A/B streptogramin antibiotics that cooperatively inhibit protein translation in Gram-positive pathogens. This review provides an overview of their discovery and bioactivity and highlights key biosynthetic and synthetic advances that have enabled analog development to address antibiotic resistance. The review is organized into five sections: IntroductionStructural assignment and biological studiesBiosynthesisSynthesisConclusion.
    Keywords:  Griseoviridin; Viridogrisein; biosynthesis; streptogramin antibiotics; total synthesis
    DOI:  https://doi.org/10.1055/a-2744-6345
  77. Front Mol Neurosci. 2026 ;19 1927505
    Stress granule phase transitions and neuronal fate in cerebral ischemia-reperfusion injury.
    Xue Liao, Li Li, Xiaohong Zhang, Qin Chen, Chunyan Guo, Jinsong Luo, Tian Wang, Zuhong Wang.
      Cerebral ischemia-reperfusion injury (CIRI) drives neuronal death through secondary molecular events that persist after blood flow is restored. How neurons commit to survival or death before individual death programs engage remains unclear. Liquid-liquid phase separation and its stress granules (SGs) offer one regulatory platform. Under CIRI stress, SGs assemble around G3BP1 and concentrate stalled mRNP complexes with RNA-binding proteins such as TDP-43, FUS, and DDX3X. The physical state of the condensate sets its function. Liquid-state SGs are cytoprotective. In a mechanism so far demonstrated outside CIRI itself, they sequester executioner caspase-3 and caspase-7. They also upregulate GPX4 protein through a G3BP1-IGF2BP1-m6A hub that limits ferroptosis. They further reduce DDX3X availability for NLRP3 inflammasome assembly, an effect now supported by direct evidence in ischemic brain tissue. When injury exceeds what liquid condensates can buffer, oxidative modification drives an irreversible liquid-to-solid transition. Cytoplasmic mislocalization of TDP-43 after nuclear pore damage, progressive FUS aggregation under sustained oxidative stress, and chaperone depletion accelerate this shift. The result is proteostasis collapse through joint failure of the ubiquitin-proteasome system and selective autophagy. Rodent occlusion models place this bifurcation in early reperfusion, broadly within the first day, though estimates remain approximate and the human interval is undefined. Muscone and icariin may stabilize acute-phase condensates, while melatonin and HDAC6 inhibition may resolve subacute aggregates. The account moves from the biophysical basis of SG formation through the distinct ischemic and reperfusion phases of assembly. It then covers the bifurcating protective and pathological trajectories before turning to therapeutic strategies and their translational limitations. This review argues that the SG checkpoint is an underappreciated node in CIRI. Progress requires defining its time window in human neurons, resolving SG behavior across the neurovascular unit, and validating topology-targeting approaches in primates.
    Keywords:  cerebral ischemia-reperfusion injury; liquid-liquid phase separation; neuroprotection; proteostasis; stress granules
    DOI:  https://doi.org/10.3389/fnmol.2026.1927505
  78. bioRxiv. 2026 Sep 19. pii: 2026.09.18.752695. [Epub ahead of print]
    METTL3 promotes human coronavirus replication through an interferon-independent mechanism.
    Ikshitaa Dinesh, Joaquim M G D Fonseca, Denise Ohnezeit, Gillian Elliott, Angus C Wilson, Hannah M Burgess.
      N6-methyladenosine (m6A) is a pervasive mRNA modification that regulates RNA fate through effects on RNA-protein interactions, stability and translation. We previously showed that replication of human betacoronaviruses, OC43 (hCoV-OC43) and SARS-CoV-2, is sensitive to depletion or pharmacological inhibition of the m6A RNA methyltransferase METTL3, resulting in reduced viral RNA and protein accumulation. In other viral systems, such antiviral effects have been attributed to enhanced interferon (IFN) signalling and interferon-stimulated gene (ISG) induction. Here, using hCoV-OC43 we show a requirement for METTL3 that is independent of canonical IFN responses. Pharmacological inhibition of METTL3 with STM2457 failed to potentiate type I IFN signalling, global ISG expression, or the non-canonical inflammatory transcriptional programme associated with OC43 infection. Furthermore, pathogen-associated RNA sensing by RIG-I or MDA5 is not required for the antiviral effect of the STM2457. ISGs reported to be most potently antiviral against OC43 are either not significantly induced by METTL3 inhibition during infection or are not required for the antiviral activity. Nevertheless, defects in viral gene expression and progression through the viral life cycle are detectable within 6 h of STM2457 treatment and host cell transcription is dispensable for STM2457 antiviral activity. Lastly, a METTL3-directed Proteolysis Targeting Chimera (PROTAC) phenocopied STM2457, producing IFN-independent antiviral activity and ruling out off-target inhibition of viral RNA methyltransferases as a plausible explanation. Together, these findings define a direct, proviral role for METTL3 in coronavirus infection consistent with a model in which METTL3-catalysed m6A modification of viral RNA is required for efficient viral life cycle progression.
    Keywords:  OC43; PROTAC; RNA modification; antiviral; coronavirus; m6A
    DOI:  https://doi.org/10.64898/2026.09.18.752695
  79. Cells. 2026 Sep 19. pii: 1701. [Epub ahead of print]15(18):
    AUG-Dependent Translation of Antisense Repeat Transcripts Contributes to Dipeptide Repeat Protein Production in C9ORF72 Expansion Carriers.
    Sandra Almeida, Yuanzheng Gu, Mark W Kankel.
      A hexanucleotide repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Bidirectional transcription of the repeat expansion generates sense and antisense RNAs that are translated into dipeptide repeat (DPR) proteins, but the mechanisms of translation initiation remain incompletely understood. Here, we used CRISPR-Cas9 genome editing and steric-blocking antisense oligonucleotides (ASOs) to investigate the role of AUG codons within the antisense repeat RNA. Deletion of an AUG-containing region upstream of the antisense repeats markedly reduced poly(GP) production without affecting antisense RNA levels, demonstrating that this sequence is required for efficient poly(GP) synthesis. We further found that unspliced sense transcripts containing the repeat expansion likely serve as templates for poly(GA) and poly(GR) production in motor neurons. Finally, ASOs targeting the antisense AUG-containing region reduced poly(PR) and poly(GP) levels without altering repeat RNA abundance, supporting a role for AUG-dependent translation of the antisense repeat RNA. These findings provide new insights into the mechanisms of DPR production and suggest that translation-blocking ASOs may represent a therapeutic strategy for C9ORF72-associated ALS/FTD.
    Keywords:  ALS; ASO; FTD; dipeptide repeat protein; iPSC-derived neurons; repeat RNA translation
    DOI:  https://doi.org/10.3390/cells15181701
  80. J Insect Physiol. 2026 Sep 25. pii: S0022-1910(26)00142-3. [Epub ahead of print] 105069
    Heat shock protein genes Hsp70 and DnaJA1 are key contributors to thermotolerance and development in predatory ladybeetle Propylaea japonica.
    Wen-Ting Sun, Jia Hu, Tong-Xian Liu, Jian-Fei Mei, Jia-Wei Sun, Shi-Ze Zhang.
      Global climate change has increased the frequency of extreme high-temperature events, underscoring the need to elucidate thermotolerance mechanisms in natural enemy insects for effective biological control. The ladybird Propylaea japonica is a predominant predator in South-East Asia and a successful biocontrol agent, yet the molecular basis of its heat resistance remains unknown. Here we cloned full-length cDNAs of three heat shock protein genes (pjhsp70, pjDnaJA1, and pjhsp21) from P. japonica using transcriptomic data. We characterized their sequences, inferred phylogenetic relationships, and quantified spatiotemporal expression by qRT-PCR across developmental stages, adult ages, and tissues. To assess function, we knocked down each gene with RNA interference (RNAi) and measured survival at 39 °C, male body weight, and sex ratio; we also expressed and purified the recombinant proteins to evaluate chaperone activity in vitro. The results showed that all three transcripts were detected throughout development, peaking in the pupal stage, and exhibited tissue-specific variation. RNAi of pjhsp70 or pjDnaJA1 markedly reduced survival under heat stress and decreased male weight while skewing the sex ratio; pjhsp21 knockdown produced no such effect. In vitro, recombinant pjhsp70 and pjDnaJA1 inhibited protein aggregation, confirming chaperone activity, whereas pjhsp21 lacked independent chaperone function. Collectively, these findings indicate that pjhsp70 and pjDnaJA1 are key contributors to thermotolerance and development in P. japonica, providing a molecular framework for enhancing biocontrol efficacy under high-temperature conditions.
    Keywords:  Biological control; Heat shock protein; Propylaea japonica; RNA interference; Thermal response
    DOI:  https://doi.org/10.1016/j.jinsphys.2026.105069
  81. Angew Chem Int Ed Engl. 2026 Sep 25. e1070299
    Molecular Details of RNA Interactions With FUS Condensates Altering Assembly, Dynamics, and Aggregation.
    Tongyin Zheng, Kandarp A Sojitra, Samara Cummings, Qizan Chen, Priyesh Mohanty, Jeetain Mittal, Nicolas L Fawzi.
      Fused in sarcoma (FUS) is an RNA-binding protein that undergoes phase separation with RNA and other cellular components, forming ribonucleoprotein (RNP) granules. While recent advances in the study of biomolecular phase separation have focused on protein-protein interactions, information on the molecular details of protein-RNA interactions within condensates remains limited. Here, we demonstrate how RNA modulates the phase separation of the low-complexity (LC) and arginine-glycine-glycine motif (RGG1) domains of FUS-low RNA concentrations enhance protein phase separation and excess RNA disrupts it. Integrating biochemical assays, NMR spectroscopy, and molecular dynamics simulations, we show that RNA incorporates into FUS condensates, reducing condensate density, drawing in water and ions, and enhancing local and diffusional motion. Whereas RNA binding in the dispersed phase primarily involves RGG1, within the condensed phase both LC and RGG1 contribute to RNA interactions. A diverse set of interactions between amino acids and RNA moieties, including prominent glutamine contacts, contributes to FUS-RNA co-condensates. RNA displaces RGG-mediated protein contacts while enhancing LC-LC interactions, providing a molecular basis for RNA-driven condensate interaction network remodeling. Furthermore, RNA accelerates the liquid-to-solid transition of FUS LC-RGG1 condensates. Together, these results provide mechanistic insight into how RNA regulates condensate assembly, dynamics, and maturation.
    Keywords:  NMR spectroscopy; intrinsically disordered protein; molecular dynamics simulation; phase separation; protein–RNA interaction
    DOI:  https://doi.org/10.1002/anie.1070299
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