bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–08–30
eighty-one papers selected by
Cédric Chaveroux, CNRS
  1. hY3 RNA binds and inhibits ribosomes and modulates the starvation-induced integrated stress response.
  2. RNA Modifications Modulate Biomolecular Condensates in Stress and Disease.
  3. RNA Modifications as Molecular Regulators of Alveolar Epithelial Injury and Aberrant Repair in Pulmonary Fibrosis.
  4. Mathematical Modeling of Dietary Timing- and Protein Quality-Responsive Liver Circadian Clock and its Function on Ribosome Biogenesis.
  5. The integrated stress response in immune thrombocytopenia: from cellular stress to hematopoietic adaptation.
  6. RNA modifications and RNA-binding proteins: interactions, regulation, and new avenues for therapeutic modulation.
  7. The Role of ZNF598 in Translational Quality Control: Mechanisms and Emerging Biological Functions.
  8. RNA Cis-Elements Involved in Animal Virus Stop Codon Readthrough: Stop Codon Context and Downstream RNA Structures.
  9. The N-terminal Extension of Ribosomal Protein Rps2 Shapes Its Early Fate through Chaperone-Importin Competition and Arginine Methylation.
  10. Translophagy-A potential link between autophagy impairment and translational errors.
  11. A Luciferase-Based Assay for Assessing Cap-Independent Translation in Wheat Germ Extract.
  12. The CCHCR1-UBAP2L Interaction Promotes UBAP2L Release from P-Bodies for Stress Granule Assembly.
  13. ELAVL1 and ELAVL4 Are Required for Musashi-Dependent Translational Activation.
  14. HuB/HuR inhibition decreases HPV E6 and E7 proteins, stabilizes p53, and induces integrated stress to impair cervical cancer cell growth.
  15. MetaTIS: a tool to predict cognate and near-cognate translation initiation sites in human.
  16. The stress-induced transcription factor ATF4 has multiple conserved retrocopies that can alter gene expression.
  17. Mutant p53 gains RNA-binding activity to reprogram translation and mitochondrial function.
  18. An axon-intrinsic loop restricts nerve regeneration through axonal protein synthesis.
  19. The Dysregulation of the Integrated Stress Response in Leukemic Stem Cells as a Marker of Treatment Sensitivity in Acute Myeloid Leukemia.
  20. Zinc increases stress granule formation by promoting RNA condensation.
  21. Mechanistic Study of m5C Modification in Stem Cell Differentiation and Disease Regulation.
  22. The Nucleolus in Human Disease: Ribosome Biogenesis, Nucleolar Surveillance, and Therapeutic Opportunities.
  23. Deciphering the comprehensive relationship between 5' UTR and 3' UTR sequences with deep learning.
  24. Paraspeckle-Mediated Integration of Nuclear RNA Regulation in Skeletal Homeostasis and Pathological Disorder.
  25. Heat shock-induced autophagy has cargo selectivity in Saccharomyces cerevisiae.
  26. Adaptive-to-maladaptive IRE1α signaling as a driver of amyloidogenic APP processing in Alzheimer's disease.
  27. Improving the dynamic range of a trimethoprim-responsive self-amplifying RNA.
  28. RNA-centered regulation in SFTSV infection: mechanisms, host interactions, and translational implications.
  29. G3BP1 depletion, observed in Parkinson's Disease, drives Golgi-lysosome-autophagy defects.
  30. RNA modifications as determinants of cancer cell death: from epitranscriptomic mechanisms to therapeutic targeting.
  31. Ribosome heterogeneity provides a translational barrier against protein misfolding disease in Saccharomyces cerevisiae.
  32. METTL3-Mediated m6A Modification of COL5A2 Inhibits Ferroptosis Through an IGF2BP3-dependent Mechanism in Gastric Cancer.
  33. m6A epitranscriptomic regulation in asthma: mechanisms and therapeutic prospects.
  34. The L-A dsRNA Virus and Its Satellites: Totiviruses and Killers in Saccharomyces cerevisiae.
  35. 16S ribosomal RNA modification drives transcript-specific translation efficiency.
  36. Targeting ADAR1 in Cancer: Biology, Therapeutic Strategies, Challenges, and Limitations.
  37. tRNA-derived small RNAs in vascular smooth muscle cell phenotypic switching and vascular remodelling.
  38. The m6A Reader YTHDC2: Molecular Mechanisms and Regulatory Networks in Disease Pathogenesis.
  39. DTT-Induced Transcriptome Profiling Reveals Divergent ER Proteostasis and Stress-Adaptation Programs in CHO-S/HB8 and CHO-4BGD/DUL Producer Clones.
  40. The AtRNC1-AtWTF1 protein complex is essential for chloroplast group Ⅱ intron splicing, ribosome biogenesis, and embryo development in Arabidopsis.
  41. Intron retention as a hub for splicing regulation in plant environmental adaptation and developmental programming.
  42. From water to land: evolution of tRNA gene repertoires in photosynthetic organisms.
  43. ZCCHC4-mediated m6A methylation regulates the UHRF1/CDO1 axis to inhibit ferroptosis and promote osteosarcoma malignant progression.
  44. The ER-Golgi intermediate compartment: a central hub integrating membrane trafficking and stress responses.
  45. Crosstalk between m6A modification and metabolic reprogramming in colorectal cancer: from the immune microenvironment to clinical applications.
  46. RNA-Binding Proteins: Function, Biological Mechanisms, and Therapeutic Opportunities.
  47. Targeting endoplasmic reticulum stress to attenuate cisplatin resistance in non-small cell lung cancer.
  48. Clusterin as a therapeutic agent: Bridging the gap in brain and eye research.
  49. A Stage-Dependent Translational Signature in Peripheral Blood Mononuclear Cells from Clinically Isolated Syndrome to Relapsing-Remitting Multiple Sclerosis: An Exploratory Cross-Sectional Study.
  50. Cell cycle-dependent translation-mediated turnover of the long noncoding RNA Malat1.
  51. Muscular dystrophy-associated lamin variants disrupt cellular organization through a nucleolar-ribosomal axis.
  52. Programmable ZBTB7A RNA N6-methyladenosine site-specific demethylation suppresses colorectal cancer liver metastasis.
  53. Epigenetic Control of Stress-Induced Depression: Emerging Roles of HDAC3 and HDAC6.
  54. Tcf15 promotes an open nucleolar chromatin state to safeguard ribosome biogenesis and genome stability in mouse embryonic stem cells.
  55. EIF2AK2 inhibits type I interferon production by inhibiting RIG-I activation and disrupting mitochondria function via recruiting VAMP8 and p-MLKL.
  56. S4 Induces Apoptosis, Cell Cycle Arrest, and Metabolic Alterations in Breast Cancer Cells.
  57. Tyrosine Supplementation Rescues a Growth Defect in a Humanized S. cerevisiae Model of YARS1 Associated with CMT-DI.
  58. The proportional scaling of mRNA and ribosome concentrations controls eukaryotic cell growth.
  59. SNHG family lncRNAs promote Ewing sarcoma cell fitness through intronic snoRNA-guided rRNA modifications.
  60. The dual role of AMPK in cancer metabolic reprogramming.
  61. Roles of SfHSP70-7 in Thermal Tolerance, Insecticide Adaptability, and Reproductive Performance Under Combined Environmental Stress of the Rice Pest Sogatella furcifera (Hemiptera: Delphacidae).
  62. MsMTA regulates growth and metabolism in alfalfa (Medicago sativa) through m6A-mediated stabilization of metabolic transcripts.
  63. The Hidden Layer of MicroRNA Regulation in Gynecologic Cancers: IsomiRs, Arm Switching, and RNA Epitranscriptomic Modifications.
  64. Small peptides play a key role as messengers in plant growth, development and abiotic stress resistance.
  65. CERES forms a complex with RH37 and eIF4E.
  66. Identification of the Site of the Fe-S Cluster in CPSF30 via Metal-Coupled Oxidation-Mass Spectrometry.
  67. Assembly of exon junction complexes on spliceosomes begins before spliceosome activation.
  68. Loss of epitranscriptomic mitochondrial RNA surveillance drives epithelial type I interferon and inflammation in autoimmunity.
  69. Oxygenaging: A Physiological Framework for Geroscience.
  70. Developing an assay system for screening inhibitors of Hfq-mediated RNA metabolism.
  71. SARS-CoV-2 Orf3a Protein Interaction Mapping Using Unnatural Amino Acid Incorporation.
  72. Convergent Mechanistic Pathways Driving the Anaplastic Phenotype in Thyroid Cancer.
  73. 5' untranslated region (5' UTR) of bovine β-globin in the mRNA constructs translates different types of antigenic proteins.
  74. RNA aptamers for sodium and lithium are abundant in mammals.
  75. Deletion of the MALAT1 RNA 3' end promotes transcript decay and inhibits proliferation in gastric and breast cancer cells.
  76. Proteostasis breakdown and aggregate diversity in aging and neurodegenerative disease.
  77. Beyond the Capsid: How Can Post-Translational Modifications Modulate the Multifunctionality of the Orthoflavivirus Capsid Protein?
  78. Beyond the Ribosome: The Expanding Role of the Nucleolus in Neurodegenerative Pathways.
  79. Mitochondria as a therapeutic platform in inflammatory and degenerative disorders: mechanisms, biomarkers, and translational challenges.
  80. RNA Splicing Dysregulation in Parkinson's Disease.
  81. Cotinine Promotes Cancer Cell Proliferation and m1A RNA Methylation in Smoking-Associated Lung Cancer by Targeting PLK1/β-Catenin/TRMT6 Axis.
  1. Nucleic Acids Res. 2026 Aug 24. pii: gkag832. [Epub ahead of print]54(16):
    hY3 RNA binds and inhibits ribosomes and modulates the starvation-induced integrated stress response.
    Valentina Pecoraro, EunBin Kong, Puneet Sharma, Yulia Gonskikh, Marek Żywicki, Fabian Nagelreiter, Markus Schosserer, Katrin Freiburghaus, Jean-Marc Nuoffer, Johannes Grillari, Norbert Polacek.
      Cells adapt to metabolic stress by orchestrating gene expression to mitigate cellular damage, sustain homeostasis, and promote survival. Within this framework, translational control provides a rapid and efficient layer of regulation. Non-coding RNAs have recently emerged as effective modulators of translation, partly by targeting the ribosome. The contribution of ribosome-associated non-coding RNAs (rancRNAs) to translation regulation, however, remains largely unexplored in human cells. Here, we identified the human Y3 (hY3) RNA as a rancRNA that inhibits protein synthesis and attenuates cellular metabolism. hY3 function was particularly critical under nutrient deprivation, where it promoted adaptive stress responses. In this context, depletion of hY3 disrupted the delicate balance between survival and apoptosis by reducing the expression of pro-survival factors and impairing the activation of the integrated stress response (ISR). Loss of hY3 reduced starvation-dependent phosphorylation of eukaryotic translation initiation factor 2α, thereby attenuating ISR signalling, which results in non-physiologically elevated global translation rates during nutrient deprivation. Together, our findings establish hY3 as a ribosome-bound regulator of translation and stress responses, positioning it as a determinant of cell fate under metabolic stress.
    DOI:  https://doi.org/10.1093/nar/gkag832
  2. Genes (Basel). 2026 08 19. pii: 973. [Epub ahead of print]17(8):
    RNA Modifications Modulate Biomolecular Condensates in Stress and Disease.
    Y Sprecher, M Sevilla-Sharon, S Moshitch-Moshkovitz.
      Biomolecular condensates are dynamic membraneless organelles composed of proteins and RNAs that assemble through multivalent interactions and provide cells with powerful means to regulate gene expression in space and time. Different epitranscriptomic marks such as m6A, m1A, and m5C can reshape RNA structure-binding interfaces and multivalency and, in this manner, tuning which transcripts nucleate or partition into specific condensates and influencing their material state. This review summarizes how individual RNA modifications and their associated proteins regulate the formation and function of BMCs such as stress granules, P-bodies, nuclear bodies and disease-linked condensates in cancer and neurodegeneration. It highlights emerging concepts of combinatorial "epitranscriptomic codes" and bidirectional feedback between condensates and RNA-modifying enzymes and discusses the current experimental and technical gaps that still limit our understanding of modification crosstalk and condensate topology.
    Keywords:  5-methylcytidine (m5C); N1-methyladenosine (m1A); N6-methyladenosine (m6A); RNA modifications; biomolecular condensates (BMCs); epitranscriptome; liquid-liquid phase separation (LLPS); multivalency
    DOI:  https://doi.org/10.3390/genes17080973
  3. Biomolecules. 2026 Aug 12. pii: 1176. [Epub ahead of print]16(8):
    RNA Modifications as Molecular Regulators of Alveolar Epithelial Injury and Aberrant Repair in Pulmonary Fibrosis.
    Qi Huang, Shuguang Wang, Yuman Huang, Shibo Xiao, Ruohan Xia, Xianwang Wang.
      Pulmonary fibrosis is a progressive interstitial lung disease characterized by persistent alveolar epithelial injury, aberrant repair, and excessive extracellular matrix deposition. Increasing evidence indicates that disease progression is closely associated with alveolar type II (AT2) cell dysfunction, impaired AT2-to-AT1 differentiation, and the persistence of transitional epithelial populations, including KRT8+ intermediate populations. Because the formation and resolution of these transitional epithelial populations require dynamic regulation of stress-responsive transcripts and differentiation-associated RNA programs, they provide a biologically relevant context for investigating RNA modification-mediated post-transcriptional regulation. RNA modifications have emerged as post-transcriptional regulatory layers that modulate RNA stability, processing, translation efficiency, and stress-response gene expression, thereby influencing epithelial stress adaptation and repair-related state transitions. Among these modifications, N6-methyladenosine (m6A) is the best-characterized layer, with evidence linking it to epithelial injury responses, senescence-associated transcript remodeling, and differentiation impairment. In contrast, non-m6A modifications, including m5C, m1A, m7G, pseudouridine (Ψ), and A-to-I RNA editing, remain emerging regulatory layers with limited AT2 cell-specific functional validation. This review summarizes current evidence connecting RNA modifications with alveolar epithelial injury, transitional-state persistence, epithelial-mesenchymal communication, and fibrotic remodeling. Rather than interpreting RNA modifications as isolated pathogenic drivers, we highlight their context-dependent roles in RNA fate control, epithelial stress adaptation, and aberrant repair in pulmonary fibrosis.
    Keywords:  AT2 cells; RNA modifications; aberrant repair; alveolar epithelial cells; epithelial–mesenchymal communication; epitranscriptomics; m6A; pulmonary fibrosis
    DOI:  https://doi.org/10.3390/biom16081176
  4. Physiol Genomics. 2026 Aug 26.
    Mathematical Modeling of Dietary Timing- and Protein Quality-Responsive Liver Circadian Clock and its Function on Ribosome Biogenesis.
    Lingjun Lu, Jordan L Levy, Tracy G Anthony, Ioannis P Androulakis.
      Independent of the suprachiasmatic nucleus, peripheral clocks can be strongly entrained by dietary signals. Although feeding time has been widely studied, the effects of food quality-particularly nutrient availability and stress-on peripheral circadian entrainment and metabolic regulation remain less understood. We developed a semi-mechanistic mathematical model of peripheral clock synchronization and clock-controlled ribosome biogenesis (RiBi) in response to feeding/fasting cycles and rhythms in dietary essential amino acid (EAA) availability. The model integrates EAA-sensitive signaling through mammalian target of rapamycin complex 1 (mTORC1) and the general control nonderepressible 2 (GCN2)-mediated integrated stress response (ISR), together with ribosomal protein expression as a metabolic endpoint. We used the model to examine circadian entrainment under nutrient stress, adaptation during transitions between feeding schedules with EAA insufficiency, and stress-related mechanisms that may restore circadian and metabolic function. Simulations showed that mTORC1 and GCN2-ISR signaling jointly regulate metabolic entrainability and stress adaptation and are required to maintain circadian synchronization and RiBi dynamics during nutrient stress. The model also predicted that differences in homeostatic adaptation can produce individualized recovery trajectories after transient dietary disruption. Finally, appropriate modulation of GCN2-ISR signaling mitigated disruption-associated RiBi hyperactivation by leveraging dietary EAA rhythms to restore clock function. These findings identify dietary EAA stress and its regulatory pathways as important determinants of peripheral circadian entrainment and metabolic adaptation, supporting the development of personalized nutrition-based strategies for circadian disruption-related chronic disease.
    Keywords:  Dietary timing; Essential amino acids; circadian entrainement; modeling; nutrient sensing
    DOI:  https://doi.org/10.1152/physiolgenomics.00152.2026
  5. Autoimmun Rev. 2026 Aug 26. pii: S1568-9972(26)00182-5. [Epub ahead of print]25(12): 104168
    The integrated stress response in immune thrombocytopenia: from cellular stress to hematopoietic adaptation.
    Xin Zhou, Yang Jiang, Shan Xu, Ningning Shan.
      Immune thrombocytopenia (ITP) is an autoimmune hematologic disorder characterized by immune-mediated platelet destruction and impaired platelet production. In addition to these core abnormalities, ITP is associated with persistent inflammation, metabolic disturbance, oxidative injury, and altered proteostasis in immune cells, megakaryocytes, platelets, and the bone marrow microenvironment. In this narrative review, we examine whether the integrated stress response (ISR) could provide a mechanistic link between these stress phenotypes and cell-specific responses in ITP. Evidence for the involvement of the four canonical eIF2α kinases is uneven and varies substantially by cell type and experimental setting. We therefore propose a cell-specific hematopoietic response model in which sustained stress inputs interact with the distinct response capacities of immune and hematopoietic cell populations. From a therapeutic perspective, we discuss current ITP treatments in terms of their established immunological or hematopoietic actions and distinguish these primary effects from secondary changes in cellular stress that may follow disease control. We also refer to some experimental methods to confirm the participation of ISR. By emphasizing these differences, the review intends to promote future mechanistic research and the assessment of possible therapeutic strategies related to stress.
    Keywords:  Endoplasmic reticulum stress; Immune regulation; Immune thrombocytopenia; Integrated stress response; Megakaryopoiesis
    DOI:  https://doi.org/10.1016/j.autrev.2026.104168
  6. RSC Chem Biol. 2026 Aug 20.
    RNA modifications and RNA-binding proteins: interactions, regulation, and new avenues for therapeutic modulation.
    Gabriela Vega-Hernández, Amanda L Garner.
      RNA-binding proteins (RBPs) are central regulators of post-transcriptional gene expression, recognizing RNAs through sequence, structure, and chemical modifications. Post-transcriptional RNA modifications, including m6A, m1A, m5C, m7G, and pseudouridine (Ψ), form the epitranscriptome, a dynamic regulatory layer that modulates RNA stability, localization, and translation. These modifications are interpreted by specialized "reader" RBPs that translate epitranscriptomic marks into functional outcomes. Dysregulation of RNA modifications or their associated reader RBPs has been increasingly linked to the development of cancers, neurological disorders, and other diseases, highlighting their potential for therapeutic manipulation. This review summarizes key RNA modifications and regulating RBPs with a specific emphasis on how dysregulation can lead to cancers. We further discuss current approaches for investigating and manipulating reader RBP-RNA interactions, highlighting how these methods enable new opportunities for therapeutic discovery.
    DOI:  https://doi.org/10.1039/d6cb00136j
  7. Biology (Basel). 2026 Aug 20. pii: 1435. [Epub ahead of print]15(16):
    The Role of ZNF598 in Translational Quality Control: Mechanisms and Emerging Biological Functions.
    Siyuan Wu, Zhiqian Liu, Guodong Chen.
      During protein synthesis, ribosome stalling, collision, and aberrant elongation can lead to the accumulation of defective nascent polypeptides and compromise cellular homeostasis. To counteract such translational disturbances, eukaryotic cells have evolved a highly conserved translational quality control network, in which the ribosome-associated quality control (RQC) pathway plays a central role in the recognition and elimination of aberrant translation complexes. Zinc Finger Protein 598 (ZNF598), a key E3 ubiquitin ligase in mammalian cells, functions as an essential factor in the early recognition and signal transduction steps of the RQC pathway. Accumulating evidence indicates that ZNF598 senses aberrant translational states, and particularly in the context of ribosome collision, mediates site-specific ubiquitination of 40S ribosomal proteins, thereby promoting ribosome splitting, nascent chain clearance, and subsequent processing of defective mRNAs. Beyond its canonical role in RQC, ZNF598 has also been implicated in the translational repression of defective mRNAs, regulation of inflammatory signaling, antiviral responses, and control of toxic translation products associated with neurodegenerative disorders. In this review, we summarize the structural features, molecular mechanisms, regulatory networks, and physiological as well as pathological functions of ZNF598. We also discuss current controversies and future directions in the field, with the aim of providing a broader framework for understanding translational quality control and its therapeutic potential.
    Keywords:  GIGYF2; ZNF598; ribosome collision; ribosome-associated quality control; translational stalling; ubiquitination
    DOI:  https://doi.org/10.3390/biology15161435
  8. Viruses. 2026 Aug 13. pii: 893. [Epub ahead of print]18(8):
    RNA Cis-Elements Involved in Animal Virus Stop Codon Readthrough: Stop Codon Context and Downstream RNA Structures.
    Nobuhiko Kamoshita.
      Stop codon readthrough is a noncanonical translation strategy employed by certain RNA viruses, in which a viral termination codon is either decoded by host near-cognate tRNAs or canonically recognized by the class I release factor (RF, eRF1 in eukaryotes). Ribosomal A-site competition between near-cognate tRNAs and eRF can shift decoding toward near-cognate tRNAs, thereby promoting non-canonical decoding events by transiently pausing termination and favoring readthrough. This review focuses on two viral cis-elements that modulate readthrough across four viral genera in which this decoding event has been experimentally validated: (i) primary sequences surrounding the stop codon (stop codon context), and (ii) downstream RNA structures. Effects of stop codon context have been observed more broadly in cellular genes, including nonsense suppression in bacteria, with mechanisms including inefficient RF association or tRNA interactions at adjacent sense codons. In eukaryotic systems, interactions with the ribosomal mRNA entry channel have been suggested. Diverse downstream structures, including gammaretroviral pseudoknots and specific structures in alpha- and coltiviruses, further stimulate readthrough in a location- and structure-sensitive manner. This effect has not been consistently observed in chikungunya and triatoviral structures, suggesting a strong dependence on local sequence and structural context. Compared with the larger number of cellular readthrough occurrences that can be detected at low efficiency by ribosome profiling, viral readthrough in mammalian systems is consistently high (>2%). Understanding the interplay between viral RNA elements and host translational machinery, including potential kinetic trapping at the termination codon, provides insights into this unusual elongation mechanism. These findings may have implications for antiviral strategies targeting these RNA elements.
    Keywords:  RNA structures; RNA virus; cis-acting RNA elements; kinetic proofreading; ribosome; stop codon readthrough; translation termination; translational recoding
    DOI:  https://doi.org/10.3390/v18080893
  9. J Biol Chem. 2026 Aug 25. pii: S0021-9258(26)02353-7. [Epub ahead of print] 113481
    The N-terminal Extension of Ribosomal Protein Rps2 Shapes Its Early Fate through Chaperone-Importin Competition and Arginine Methylation.
    Maximilian Mack, Benjamin Pillet, Nicole Holton, Ingrid Zierler, Stephanie Himpich, Phyllis Jessen, Markus C Wahl, Dieter Kressler, Brigitte Pertschy.
      Efficient nuclear import of ribosomal proteins is essential for the timely assembly of ribosomal subunit precursors in the nucleus and progression of ribosome biogenesis. Several ribosomal proteins are escorted to the nucleus by dedicated chaperones, which shield their interaction surfaces and assist their delivery. Here, we characterize the N-terminal extension of the small subunit ribosomal protein Rps2 as a regulatory hub that integrates binding of its dedicated chaperone Tsr4, recognition by its importin Pse1, and arginine methylation. By mapping Pse1's interaction interface on Rps2's N-terminal extension, we identified arginine 11 (R11), a known methylation site, as a critical residue. We demonstrate that Rps2 is already methylated while associated with Tsr4, indicating that methylation occurs at an early stage of the Rps2 assembly path prior to nuclear import. We further show that the chaperone Tsr4 and the importin Pse1 compete for binding to the Rps2 N-terminal extension. While Tsr4 binds this region with higher affinity than Pse1, Pse1 also contacts additional regions within full-length Rps2. Arginine methylation of Rps2 modestly reduces Pse1 binding to the Rps2 N-terminal extension, while having little effect on Tsr4 binding, suggesting that this modification can influence importin recognition without disrupting chaperone association. Finally, we find that Rps2 methylation increases at low temperature and that loss of Hmt1-mediated methylation exacerbates translational fidelity defects in an rps2 mutant background. Together, our findings reveal how a ribosomal protein N-terminal extension coordinates sequential interactions and post-translational modification events that shape the early fate of Rps2 and support accurate ribosome function.
    Keywords:  Hmt1; Rps2; Saccharomyces cerevisiae; Tsr4; nuclear transport; post‐translational modification (PTM); protein arginine methylation; protein methylation; protein‐protein interaction; ribosome assembly
    DOI:  https://doi.org/10.1016/j.jbc.2026.113481
  10. FEBS Lett. 2026 Aug 27.
    Translophagy-A potential link between autophagy impairment and translational errors.
    Mykola V Korolchuk, Gailing Ma, Robin Antrobus, Diego Manni, Marco Trevisan-Herraz, Mustafa Khwaja, Max Brown, Gavin D Richardson, Masaaki Komatsu, Daniel Erskine, Viktor I Korolchuk, Tetsushi Kataura.
      Maintenance of protein homeostasis requires coordination between protein synthesis and degradation, yet whether autophagy directly controls translational machinery remains unclear. Here we explored whether autophagy maintains translational fidelity. Proteomic analysis of ubiquitin-enriched fractions and p62-associated proteins in autophagy-deficient tissue confirmed previous studies identifying ribosomal proteins and RNA-binding factors among candidate autophagy cargo. Pharmacological or genetic impairment of autophagy increased translational errors, particularly during oxidative stress. Components of the translational machinery localised to LC3-positive autophagic structures and accumulated in human brain tissue affected by neurodegeneration. These findings support a hypothesis in which autophagy preserves protein synthesis quality by removing damaged translational machinery. We term this proposed mechanism translophagy, potentially linking autophagy dysfunction, oxidative stress and the aberrant proteins in neurodegenerative disease.
    Keywords:  ageing; aggregation; autophagy; mRNA; neurodegeneration; oxidative stress; ribosome; translation
    DOI:  https://doi.org/10.1002/1873-3468.70448
  11. Bio Protoc. 2026 Aug 20. 16(16): e5791
    A Luciferase-Based Assay for Assessing Cap-Independent Translation in Wheat Germ Extract.
    Max Cortot, Thorsten Stehlik, Aline Koch, Timo Schlemmer.
      Efficient protein synthesis in eukaryotic cells typically requires a 5' cap structure on messenger RNAs (mRNAs). However, under stress conditions or in viral infection, translation can also occur independently of the cap via internal ribosomal entry sites (IRES). IRES elements are therefore key regulators of protein expression in both viral and cellular contexts. Here, we describe a cell-free protocol to quantitatively assess cap-independent translation using wheat germ extract (WGE) and a firefly luciferase (FLuc) reporter. The protocol includes template preparation, RNA synthesis, and luminescence measurement following in vitro translation in WGE. This method enables rapid and robust comparison of translation activity under controlled conditions and can additionally be applied to evaluate mRNA modifications designed to enhance translation efficiency. Key features • Stringent in vitro workflow from DNA template preparation through RNA synthesis and protein synthesis to reporter readout, including quality controls. • Evaluation of cap-independent translation suitable for testing combinations of IRES and CDS. • Translation analysis without radioactive labeling.
    Keywords:  Cap-independent translation; Firefly luciferase reporter; IRES; In vitro translation; Internal ribosomal entry site; Translation efficiency; Wheat germ extract; mRNA modification
    DOI:  https://doi.org/10.21769/BioProtoc.5791
  12. Int J Mol Sci. 2026 Aug 20. pii: 7451. [Epub ahead of print]27(16):
    The CCHCR1-UBAP2L Interaction Promotes UBAP2L Release from P-Bodies for Stress Granule Assembly.
    Zhaohui Ye, Mingze Xu, Chun Lin, Stephen Cho Wing Sze, Chunman Li.
      Ribonucleoprotein granules such as processing bodies (P-bodies) and stress granules (SGs) are membrane-less organelles that regulate mRNA metabolism through liquid-liquid phase separation. UBAP2L drives SG assembly and can bridge P-bodies with SGs, yet how it is mobilized between these compartments remains unclear. Here, using co-immunoprecipitation, GST pull-down, CRISPR-Cas9-mediated knockout, and immunofluorescence microscopy, we demonstrate that CCHCR1 directly binds UBAP2L and that this interaction is dynamically regulated by stress intensity. Under mild oxidative stress, CCHCR1 retains UBAP2L in P-bodies; as stress intensifies, this interaction weakens, permitting UBAP2L release for SG assembly. CCHCR1 deficiency aberrantly traps UBAP2L in P-bodies via enhanced DDX6 association, resulting in defective SG assembly, delayed maturation, and increased P-body-SG fusion. These findings establish CCHCR1 as a stress-responsive switch that controls UBAP2L partitioning between P-bodies and stress granules, thereby controlling the threshold and kinetics of SG biogenesis.
    Keywords:  CCHCR1; RNA granule dynamics; UBAP2L; liquid–liquid phase separation
    DOI:  https://doi.org/10.3390/ijms27167451
  13. Biomolecules. 2026 Jul 31. pii: 1119. [Epub ahead of print]16(8):
    ELAVL1 and ELAVL4 Are Required for Musashi-Dependent Translational Activation.
    Katherine Bronson, Milla M Reddick, Kenzie B Macnicol, Cole Bolen, Linda Hardy, Alex Lagasse, Angela K Odle, Gwen V Childs, Melanie C MacNicol, Angus M MacNicol.
      The RNA-binding proteins Musashi1 and Musashi2 (MSI1 and MSI2) regulate stem cell function and tissue plasticity by modulating mRNA translation. While typically known as translational repressors, the MSI1 and MSI2 proteins can also act as context-dependent activators of mRNA translation, although the mechanism of MSI-mediated translational activation is unknown. Here, we identify Embryonic Lethal Abnormal Vision-like (ELAVL) proteins as essential co-regulators of MSI1-dependent translational activation. In Xenopus laevis oocytes, antisense oligonucleotide knockdown of Elavl4 inhibited progesterone-stimulated maturation and blocked polyadenylation and translation of key MSI target mRNAs, including the Mos and Cyclin B5 mRNAs. Exogenous expression of ELAVL4 rescued these defects, confirming its necessity for maturation and cell cycle progression. Mechanistically, we determined that the ELAVL4 C-terminal domain interacts with the N-terminal RNA recognition motifs of MSI1 in an RNA-independent manner. Mass spectrometry and functional assays revealed this interaction is evolutionarily conserved: mouse ELAVL1 interacts with MSI1 in the pituitary, and human ELAVL1 rescues Elavl4-depleted Xenopus oocytes. Furthermore, knockdown of Elavl1 in a mammalian cell line abrogated MSI-dependent translational activation of a pituitary Prop1 3' UTR mRNA reporter. Our results establish a conserved mechanism where ELAVL family members interact with MSI to promote MSI-dependent mRNA translational activation.
    Keywords:  ELAVL; MSI; mRNA translation; oocyte; pituitary
    DOI:  https://doi.org/10.3390/biom16081119
  14. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2401248123
    HuB/HuR inhibition decreases HPV E6 and E7 proteins, stabilizes p53, and induces integrated stress to impair cervical cancer cell growth.
    Xisheng Liu, Saroj Kumar Shrestha, Yvonne J K Edwards, Natalia Filippova, Charles N Landen, Donald J Buchsbaum, Louis B Nabors, Louise T Chow, N Sanjib Banerjee.
      High-risk human papillomaviruses (HR-HPVs) cause 95% of cervical cancers (CaCx) and a significant fraction of other anogenital and oropharyngeal cancers. Transcriptomic analyses have revealed that HR-HPVs differentially induce RNA binding proteins (RBPs) associated with cancer-related pathways. One of them, ELAVL2/HuB, is related to the ubiquitous, well-studied ELAVL1/HuR. But the role of either RBP in HPV pathobiology is unclear. In this study, we examined SRI-42127, an inhibitor of HuR, for its ability to curb CaCx growth in multiple model systems. We report that HR-HPV E6 and E7 oncogenes regulate the abundance and localization of HuB and HuR, that these two RBPs form a heterodimer, and that their genes are transcriptionally linked. We show that SRI-42127 reduces both RBPs, disrupts cell cycle regulation, and induces apoptosis in CaCx cell lines. We attribute these effects to a previously unrecognized ability to induce DNA damage and integrated stress response (ISR), resulting in decreased HPV E6 and E7 transcripts and proteins, while stabilizing transcriptionally active p53. Using siRNA knockdown, our results confirm that the reduction of HuB and HuR causes DNA damage and induces ISR. Furthermore, SRI-42127 curtails tumor growth of HPV16+/hRasG12V transformed mouse TC-1 cells in syngeneic mice. Additionally, SRI-42127 complements cisplatin in inhibiting the growth of a CaCx cell line in 3D cultures and patient-derived xenografts in SCID mice. Collectively, these findings indicate that, by decreasing RBPs, while inducing DNA damage and ISR, SRI-42127 reduces HPV oncoproteins, restores p53 function in HPV+ CaCxs, thereby enhancing their sensitivity to conventional chemotherapy.
    Keywords:  DNA-damage; HuB HuR; SRI-42127; cervical cancer; integrated stress response
    DOI:  https://doi.org/10.1073/pnas.2401248123
  15. NAR Genom Bioinform. 2026 Sep;8(3): lqag100
    MetaTIS: a tool to predict cognate and near-cognate translation initiation sites in human.
    Aram Papazian, Volkhard Helms.
      Ribosomes typically commence translation at a methionine-encoding AUG codon flanked by a so-called Kozak region, a short nucleic acid motif that serves as an initiation site in humans. Though, the characteristic AUG start codon of an mRNA is not always effective in initiating translation. Near-cognate codons differing from AUG by one nucleotide may also be recognized as start sites. Several types of ribosomal profiling techniques have been developed that elucidate active translation initiation sites (TIS) that enable training of computational models to predict both cognate and near-cognate TIS using mRNA sequence features. Here, a meta-model termed MetaTIS was implemented by combining outputs of genomic and protein language models fine-tuned on Ensembl annotations of transcripts and five different TIS datasets. The model proficiently differentiates between spurious and true TIS in four distinct test sets, for both AUG and non-AUG instances. Most important for translation initiation based on one of the base model outputs was the Kozak sequence context and a region further upstream in the 5'UTR [-12, -10]. MetaTIS is available as a webserver at https://service2.bioinformatik.uni-saarland.de/metatis/, a tool that accurately predicts TIS for AUG and nine near-cognate start codons.
    DOI:  https://doi.org/10.1093/nargab/lqag100
  16. HGG Adv. 2026 Aug 27. pii: S2666-2477(26)00106-5. [Epub ahead of print] 100666
    The stress-induced transcription factor ATF4 has multiple conserved retrocopies that can alter gene expression.
    Hans M Dalton, Elizabeth M Brydon, Tiffany S Chan, Katie G Owings, Mandi M L Wild, Naomi J Young, Clement Y Chow.
      The cell must defend against various stressors from internal and external sources that disrupt cell homeostasis. The integrated stress response (ISR) is a highly conserved pathway that helps restore this homeostasis through upregulating the transcription factor, ATF4. Despite its importance to cell health and human disease, ATF4 has several duplications in humans that have not been characterized. Here, we characterize four retroduplications (retrocopies) of ATF4 in humans. Evolutionary analysis demonstrates that these retrocopies are present and intact in many primate species over the past 37 million years, including several independent copies. We also find evidence of non-neutral evolution among primates. Human ATF4 retrocopies show basal transcription in healthy, unstressed cells and can be upregulated by the ISR. When translated in human cells, ATF4 retrocopy proteins are regulated by the proteasome in the same way as the parent ATF4 protein. Remarkably, each retrocopy can also alter the expression of several canonical ATF4 target genes, demonstrating that they can impact ISR-ATF4 stress signaling. Overall, ATF4 retrocopies are conserved, biologically functional, and should be considered in future studies of the ISR and ATF4.
    DOI:  https://doi.org/10.1016/j.xhgg.2026.100666
  17. Cell Rep. 2026 Aug 18. pii: S2211-1247(26)00934-4. [Epub ahead of print]45(8): 117856
    Mutant p53 gains RNA-binding activity to reprogram translation and mitochondrial function.
    Wuyue Zhou, Alice Long, Cameron J Douglas, Dalila Gallegos, James M Burke, David W C MacMillan, Ezgi Hacisuleyman, Ciaran P Seath.
      Tumor suppressor p53 is a transcription factor mutated in ∼50% of cancers. Somatic mutations in the DNA-binding domain abolish tumor suppression and thus lead to a loss-of-function activity, while a small subset of recurrent "hotspot" mutants have been shown to confer gain-of-function activities. Using an intein-based μMap photoproximity labeling approach, we map the interactomes of five hotspot mutants and find that mutant p53 (mut p53) acquires interactions with RNA-binding proteins, shifts toward the cytoplasm, and shows increased proximity to structured RNA and RNA-binding proteins. CLIP (Cross-linking and immunoprecipitation) experiments show that mut p53 possesses an RNA-binding motif and is enriched at 3'UTRs, promoting ribosomal localization and localization at the mitochondrial surface. Using ribosome profiling, we further show that mut p53 alters translation and promotes changes in miRNA processing and mitochondrial function, providing a mechanistic rationale for historically reported but poorly understood phenotypes.
    Keywords:  CLIP-seq; CP: cancer; CP: molecular biology; RNA binding; cancer; gain-of-function; mitochondria; mutant p53; proximity labeling; ribosome profiling; translation; μMap
    DOI:  https://doi.org/10.1016/j.celrep.2026.117856
  18. Sci Adv. 2026 Aug 28. 12(35): eaed0049
    An axon-intrinsic loop restricts nerve regeneration through axonal protein synthesis.
    Courtney N Buchanan, Jinyoung Lee, Samaneh Matoo, Jordan A Headen, Marie-Claire Honoree, Molly Conway, Lillian F Thompson, Terika P Smith, Ansley McKay, Cailyn Tosadori, Irene Dalla Costa, Moira Lopez De Leon, Elizabeth Thames, Nora Perrone-Bizzozero, Ashley L Kalinski, Kristy Welshhans, Lauren S Vaughn, Jeffery L Twiss.
      Injured axons synthesize the RNA Binding Protein KHSRP that promotes mRNA decay and slows nerve regeneration. Axotomy-induced increase in axoplasmic Ca2+ activates axonal Khsrp translation, and while axonal Ca2+ returns to pre-injury levels within 16 hours post-axotomy, axonal KHSRP remains elevated. Alternating translation of Reg3a and Khsrp sustains KHSRP levels in regenerating axons. Axonal Reg3a mRNA and protein increase proximal to the injury site days after sciatic nerve crush. REG3A stimulates ER Ca2+ release in axons to activate PERK, increase eIF2α phosphorylation, and increase Khsrp translation. Axoplasmic Ca2+ slowly oscillates in growth cones of cultured neurons and Reg3a depletion attenuates growth cone Ca2+ oscillations, decreases KHSRP synthesis and reduces axonal retractive events in cultured neurons, and accelerates peripheral nerve regeneration in vivo. Thus, REG3A regulation of axonal KHSRP synthesis provides a signaling loop that decelerates axon growth through localized mRNA translation.
    DOI:  https://doi.org/10.1126/sciadv.aed0049
  19. Genes (Basel). 2026 08 14. pii: 954. [Epub ahead of print]17(8):
    The Dysregulation of the Integrated Stress Response in Leukemic Stem Cells as a Marker of Treatment Sensitivity in Acute Myeloid Leukemia.
    Giorgia Benedetta Dutti, Katia Mangialardi, Simona Rasola, Ludovico Sebastio, Francesco Tarantini, Cosimo Cumbo, Luisa Anelli, Antonella Zagaria, Nicoletta Coccaro, Angela Minervini, Giuseppina Tota, Immacolata Redavid, Maria Rosa Conserva, Pellegrino Musto, Francesco Albano.
      Acute myeloid leukemia (AML) persistence is sustained by leukemic stem cells (LSCs) that survive metabolic deprivation, oxidative stress, hypoxia, proteotoxic burden, and therapeutic pressure. The integrated stress response (ISR) has emerged as a central adaptive network in this process. Through phosphorylation of a subunit of eukaryotic initiation factor 2 (eIF2α) and selective translation of activating transcription factor 4 (ATF4), the ISR coordinates stress-responsive transcriptional programs that may either preserve cellular fitness or promote apoptotic commitment, depending on the intensity, duration, and biological context of activation. In AML, ATF4 occupies a critical position at the interface between stemness, metabolic adaptation, redox control, ferroptosis resistance, and treatment response. In primitive leukemic compartments, ISR-ATF4 signaling appears to support stress tolerance, amino acid metabolism, serine biosynthesis, autophagy, and leukemic persistence. At the same time, pharmacologic or sustained ISR activation may lower the apoptotic threshold by inducing pro-apoptotic mediators such as CHOP, PUMA, and NOXA, thereby modulating MCL-1 dependency and enhancing sensitivity to venetoclax-based strategies. Conversely, adaptive ISR signaling may promote resistance through mechanisms such as ATP-binding cassette subfamily B member 1 (ABCB1) enhancer activation and mitochondrial stress tolerance. This duality creates a therapeutic paradox: ISR-ATF4 signaling may need to be inhibited in adaptive, resistance-promoting states but amplified in apoptosis-permissive contexts. This review discusses the biological and therapeutic relevance of ISR-ATF4 dysregulation in AML and highlights the need for biomarkers capable of distinguishing adaptive ATF4 dependency from inducible apoptotic vulnerability.
    Keywords:  ATF4; ISR; activating transcription factor 4; acute myeloid leukemia; integrated stress response
    DOI:  https://doi.org/10.3390/genes17080954
  20. Cell Rep. 2026 Aug 24. pii: S2211-1247(26)00948-4. [Epub ahead of print]45(9): 117870
    Zinc increases stress granule formation by promoting RNA condensation.
    Luisa Macedo de Vasconcelos, Nina Ripin, Roy Parker.
      During cellular stress, mRNAs are condensed into stress granules through the action of G3BP1 and G3BP2. How intracellular conditions affect RNA-protein condensation in stress granules is still unclear. Herein, we present several observations that cells modulate intracellular zinc concentrations to reduce the direct impact of zinc on RNA condensation. We show that oxidative stress increases the intracellular labile zinc and the expression of zinc-sequestering proteins, metallothioneins. Increased intracellular zinc leads to increased stress granule formation and delays stress granule disassembly without increasing translational repression, while zinc depletion decreases stress granule formation, demonstrating that even endogenous levels of free zinc can affect granules. Mechanistically, we demonstrate how zinc promotes stress granule formation by directly stimulating RNA condensation interactions at 100× lower concentrations than magnesium. Together, these data indicate that zinc modulates RNA condensation and stress granule formation and implies an unappreciated potential role for zinc in modulating intracellular RNA structures and interactions.
    Keywords:  CP: cell biology; CP: molecular biology; RNA condensation; oxidative stress; stress granules; zinc
    DOI:  https://doi.org/10.1016/j.celrep.2026.117870
  21. Stem Cell Rev Rep. 2026 Aug 29.
    Mechanistic Study of m5C Modification in Stem Cell Differentiation and Disease Regulation.
    Xiangrong Zhang, Jianqiao Li, Zhifeng Zhang, Xueqian Chen, Jiankai Yang, Wei Liu.
      m5C (5-methylcytosine) modification is a significant epigenetic modification in RNA that has garnered substantial attention in recent years in stem cell biology and disease research. The dynamic regulation of m5C involves methyltransferases, demethylases, and specific binding proteins, which collectively influence RNA stability, translation efficiency, and cellular function. Especially in stem cell differentiation, m5C modification not only affects stem cell self-renewal and differentiation fate but is also closely associated with the onset and progression of various diseases. This review explores the mechanisms of m5C modification in stem cell differentiation and related diseases, highlighting its emerging roles in gene expression regulation and disease pathogenesis. CLINICAL TRIAL NUMBER: Not applicable.
    Keywords:  Disease; M5C; Methylation Modification; Stem Cell Differentiation
    DOI:  https://doi.org/10.1007/s12015-026-11222-5
  22. Biomolecules. 2026 Jul 31. pii: 1121. [Epub ahead of print]16(8):
    The Nucleolus in Human Disease: Ribosome Biogenesis, Nucleolar Surveillance, and Therapeutic Opportunities.
    Olivia Delfino, Jiachen Xuan, Nadine Hein, Rita Ferreira, Ross D Hannan, Amee J George.
      The nucleolus has emerged as a dynamic and multifunctional subnuclear organelle that integrates ribosome biogenesis with cellular growth and stress signalling. Dysregulation of nucleolar function is increasingly recognised as a central driver of human disease, linking altered ribosome production and nucleolar surveillance pathways to cancer, ribosomopathies, premature ageing syndromes, neurodegeneration, and immune disorders. In this review, we integrate structural, molecular, and disease-level perspectives on nucleolar biology to define how ribosome biogenesis and nucleolar surveillance regulate cellular state across physiological and pathological contexts, positioning the nucleolus as an active regulator of cell function. We outline areas of convergence, identify key unresolved questions, and highlight therapeutic vulnerabilities that arise, including opportunities for small-molecule inhibitors and gene-based approaches.
    Keywords:  cancer; nucleolar stress response; nucleolar surveillance pathway; nucleolus; ribosome biogenesis; ribosomopathies; therapeutics
    DOI:  https://doi.org/10.3390/biom16081121
  23. Bioinformatics. 2026 Aug 26. pii: btag634. [Epub ahead of print]
    Deciphering the comprehensive relationship between 5' UTR and 3' UTR sequences with deep learning.
    Kanta Suga, Keisuke Yamada, Michiaki Hamada.
       MOTIVATION: Recent advances in mRNA therapeutics have driven further research on the untranslated regions (UTRs) of mRNA. However, prior studies have mainly focused on either the 5' or 3' UTR individually. Increasing evidence suggests potential cooperative effects between these two regions, which remain largely unexplored in computational studies.
    RESULTS: We present a deep learning-based approach to predicting relationships between 5' and 3' UTRs by leveraging latent representations from a pre-trained RNA language model and contrastive learning. Our method effectively identifies highly related UTRs, uncovering sequence and expression characteristics that suggest functional interplay. Our analysis revealed that Highly Related UTRs (HRUs) are significantly enriched in genes associated with neural development, exhibit distinctive UTR length and secondary structure characteristics, and are involved in cell type-specific regulation of translation efficiency. These findings provide new insights into UTR co-optimization for mRNA therapeutics.
    AVAILABILITY: The source code is available for free at https://github.com/hmdlab/utr\_pairpred.git. The data and intermediate files used in our analysis are available at https://waseda.box.com/v/utr-pairpred-data.
    DOI:  https://doi.org/10.1093/bioinformatics/btag634
  24. Calcif Tissue Int. 2026 Aug 24. pii: 131. [Epub ahead of print]117(1):
    Paraspeckle-Mediated Integration of Nuclear RNA Regulation in Skeletal Homeostasis and Pathological Disorder.
    Liangliang Wei, Yan Zhang, Dageng Huang.
      Paraspeckles are NEAT1_2-dependent nuclear ribonucleoprotein condensates that regulate gene expression through RNA retention, protein sequestration, transcriptional control, and RNA processing. This review systematically summarizes paraspeckle organization and examines the roles of NEAT1 isoforms and paraspeckle-associated proteins in diverse skeletal diseases. By integrating evidence from osteoporosis, osteoarthritis, osteosarcoma, and intervertebral disc degeneration, we outline how paraspeckle-related pathways influence skeletal cell differentiation, stress responses, and disease progression. The strongest direct evidence comes from osteoblasts, in which mechanically induced NEAT1_2-dependent paraspeckles retain Smurf1 mRNA in the nucleus, reduce SMURF1 translation, stabilize RUNX2, and promote osteoblast function. In other skeletal contexts, however, many studies have examined total NEAT1 without directly verifying intact paraspeckle function. By distinguishing these levels of evidence, this review clarifies current mechanistic understanding and highlights the therapeutic potential of paraspeckle-related pathways in skeletal disorders.
    Keywords:  Osteoarthritis; Osteoporosis; Osteosarcoma; Paraspeckle
    DOI:  https://doi.org/10.1007/s00223-026-01593-9
  25. Autophagy. 2026 Aug 26.
    Heat shock-induced autophagy has cargo selectivity in Saccharomyces cerevisiae.
    Dimitra Dialynaki, Yuxiang Huang, Daniel J Klionsky.
      Mechanisms aimed at recovering from heat-induced damage are closely associated with the organism's ability to survive extreme temperature exposure. In such a scenario, we show that autophagy, as a cytoprotective mechanism, ensures recovery and viability after induced heat stress in Saccharomyces cerevisiae. Our findings indicate that heat shock triggers the targeted degradation of ubiquitinated protein aggregates, mediated by the macroaggrephagy receptor Cue5. Moreover, heat stress induces the turnover of the aggrephagy receptor Cct2 and the polyglutamine repeats of the HTT (huntingtin) protein (polyQ-HTT). Notably, even though Cct2 and polyQ-HTT degradation is vacuole-dependent, it is mediated autonomously of canonical autophagy pathways. Collectively, this study demonstrates a novel role of autophagy in maintaining protein homeostasis after heat stress in yeast and provides insights into the potential medical applications of heat treatment.
    Keywords:  Aggrephagy; Cct2; Cue5; autophagy; budding yeast; heat stress; polyQ-HTT
    DOI:  https://doi.org/10.1080/15548627.2026.2724473
  26. Front Mol Biosci. 2026 ;13 1903849
    Adaptive-to-maladaptive IRE1α signaling as a driver of amyloidogenic APP processing in Alzheimer's disease.
    Daniel Wang, Qinan Yin.
      Alzheimer's disease (AD) is increasingly recognized as a disorder of proteostatic failure characterized by progressive disruption of neuronal protein quality control, culminating in amyloid-β (Aβ) accumulation and synaptic dysfunction. Chronic activation of the endoplasmic reticulum (ER) stress response represents one of the earliest molecular alterations detected in vulnerable brain regions and correlates with Braak progression before overt plaque deposition. Inositol-requiring enzyme 1 alpha (IRE1α), the most evolutionarily conserved sensor of the unfolded protein response (UPR), functions as a signaling rheostat within this network through its divergent downstream outputs. Under moderate proteotoxic stress, adaptive IRE1α- X-box binding protein 1 (XBP1) signaling supports ER proteostasis, preserves amyloid precursor protein (APP) quality control, and favors non-amyloidogenic α-secretase processing. Persistent ER stress, however, drives sustained IRE1α hyperactivation and engages regulated IRE1α-dependent decay (RIDD), which destabilizes microRNA (miRNA) networks that normally constrain beta-site APP-cleaving enzyme 1 (BACE1) expression, thereby favoring amyloidogenic APP processing. Accumulating evidence suggests that aging progressively compromises ER proteostatic capacity, thereby redirecting IRE1α signaling away from adaptive XBP1s-mediated responses toward a predominantly RIDD-driven state. This shift may reinforce a self-sustaining cycle in which accumulating Aβ further amplifies ER stress signaling. Here, we examine how dynamic changes in IRE1α signaling bias contribute to amyloidogenic progression in AD and consider whether selective modulation of adaptive versus maladaptive IRE1α outputs may offer stage-dependent therapeutic benefit.
    Keywords:  APP processing; Alzheimer’s disease; BACE1; ER stress; IRE1α; RIDD; XBP1s; amyloid-β
    DOI:  https://doi.org/10.3389/fmolb.2026.1903849
  27. RNA. 2026 Aug 28. pii: rna.080982.126. [Epub ahead of print]
    Improving the dynamic range of a trimethoprim-responsive self-amplifying RNA.
    Pieter Vervaeke, Francis Combes, Niek Sanders.
      Self-amplifying mRNA (SAM) is a potential platform for protein replacement, as it enables recipients to transiently produce a therapeutic protein for 4-8 weeks. To obtain external control over the level and duration of protein expression, synthetic SAM constructs that switch OFF in the presence of a small molecule such as trimethoprim (TMP) have been developed in the past. Here, we increase the ON-state protein expression of such a TMP-responsive SAM by fusing the effector protein L7Ae to a TMP-responsive destabilizing domain (DD) on both terminals. We also lower the OFF-state by adding a duplicate of the SAM 3'UTR downstream of the DD-L7Ae subgenomic ORF. We demonstrate that fusing two DDs to L7Ae has a beneficial effect on the response rate and level of protein production after removal or addition of TMP. We further demonstrate that overexpression of DD-L7Ae results in microscopic abnormalities. These insights are implemented in a mechanistic model, and further improvements of the platform are highlighted.
    Keywords:  Engineered RNA platform; K-turn; L7Ae; Self-amplifying RNA; Trimethoprim
    DOI:  https://doi.org/10.1261/rna.080982.126
  28. Virol Sin. 2026 Aug 22. pii: S1995-820X(26)00140-9. [Epub ahead of print]
    RNA-centered regulation in SFTSV infection: mechanisms, host interactions, and translational implications.
    Aofan Wang, Jiale Li, Lin Chen, Baoyin Su, Jiapei Han, Ke Zhang, Yuxin Chen.
      Severe fever with thrombocytopenia syndrome virus (SFTSV) is an emerging tick-borne pathogen that causes substantial morbidity and high case fatality in severe cases, representing a major public health concern in East Asia. Although protein-mediated mechanisms of SFTSV replication and immune evasion have been extensively studied, accumulating evidence indicates that viral infection is also influenced by RNA-centered regulatory processes. These processes include viral RNA transcription and replication, epitranscriptomic modification, host RNA-binding proteins, RNA interference-related pathways, small RNA responses, and NSs-driven inclusion bodies. Current evidence is strongest for L protein-mediated viral RNA transcription and replication, m6A-related regulation of viral RNA stability and translation, selected host RNA-binding proteins involved in viral RNA metabolism, and NSs-mediated antagonism of AGO2-dependent RNA interference and antiviral signaling. In contrast, the direct role of m6A in innate immune sensing, the functional significance of virus-derived microRNA-like small RNAs, and the physical protection of viral RNA within NSs-driven condensates remain incompletely established. In this review, we summarize current knowledge of how RNA-centered mechanisms regulate SFTSV RNA fate, viral replication, host adaptation, immune antagonism, and cross-host transmission. We further discuss their potential implications for biomarker discovery and antiviral development, while emphasizing the uneven strength of evidence and the mechanistic and translational barriers that remain. An evidence-stratified RNA-centered framework may help prioritize future studies and guide the rational exploration of RNA-based diagnostic and therapeutic strategies for SFTSV infection.
    Keywords:  NSs-driven inclusion bodies; RNA-binding proteins; RNA-centered regulation; Severe fever with thrombocytopenia syndrome virus (SFTSV); m(6)A modification
    DOI:  https://doi.org/10.1016/j.virs.2026.08.011
  29. Cell Death Differ. 2026 Aug 26.
    G3BP1 depletion, observed in Parkinson's Disease, drives Golgi-lysosome-autophagy defects.
    Sarayu Ramakrishna, Laura Ryan, Sung Min Son, David C Rubinsztein.
      The RNA binding G3BP1 is depleted in several neurodegenerative diseases, yet its functional consequences at the cellular level remain poorly understood. While best known for its critical role in stress granule formation, we demonstrate that G3BP1 also stabilises the COPI vesicle protein beta-COP by promoting its interaction with the deubiquitinase USP10. G3BP1 depletion disrupts this interaction leading to increased ubiquitination of beta-COP, which accelerates its proteasomal degradation. This leads to compromised Golgi structure and function, and impaired lysosomal homeostasis, which causes defective autophagic flux. Consequently, the autophagic clearance of α-synuclein, a protein that can drive Parkinson's disease (PD), is significantly slowed. Importantly, we observe a concurrent reduction of both G3BP1 and beta-COP protein levels in brain sections from PD and dementia with Lewy Body (DLB) patients and from a PD mouse model. These findings reveal a novel mechanistic link between G3BP1, vesicular trafficking, and proteostasis in neurodegeneration.
    DOI:  https://doi.org/10.1038/s41418-026-01853-z
  30. Funct Integr Genomics. 2026 Aug 27. pii: 236. [Epub ahead of print]26(1):
    RNA modifications as determinants of cancer cell death: from epitranscriptomic mechanisms to therapeutic targeting.
    Anirban Goutam Mukherjee, Ankit Kumar Bharti, Deepthi Maria Mathew, Bhavani Manoj Varma, Sristy Pradhan, Abilash Valsala Gopalakrishnan.
      Epitranscriptomics has rapidly evolved into a central layer of post-transcriptional gene regulation in cancer, yet its mechanistic contribution to regulated cell death remains incompletely resolved. This review critically examines how RNA modifications principally N⁶-methyladenosine (m⁶A), alongside 5-methylcytosine (m5C), N⁷-methylguanosine (m⁷G), pseudouridylation (Ψ), and adenosine-to-inosine (A-to-I) editing reprogram apoptotic and ferroptotic thresholds in malignant cells. It highlights that m⁶A does not exert uniform effects; rather, outcomes are dictated by site specificity, reader stoichiometry, and cellular context, with opposing roles observed in the regulation of BCL-2 family signaling and the SLC7A11-GPX4 antioxidant axis. The analysis extends beyond m⁶A to evaluate emerging, yet often under-validated, evidence implicating m5C in ferroptosis resistance, A-to-I editing in immune evasion, and m⁷G/Ψ in translational control of survival programs. Importantly, the review integrates tumor microenvironmental pressures including hypoxia, reactive oxygen species, and immune signaling-as dynamic modulators of epitranscriptomic machinery, thereby linking RNA chemistry to adaptive stress responses and therapeutic resistance. Despite rapid technological advances, including MeRIP-seq, crosslinking-based mapping, and nanopore direct RNA sequencing, the field remains constrained by limited resolution, lack of quantitative stoichiometry, and insufficient site-specific functional validation. Many conclusions are derived from global perturbation of epitranscriptomic enzymes, obscuring causal attribution to individual modified transcripts. From a translational perspective, targeting writers, erasers, and readers offers promise for sensitizing tumors to cell death; however, pleiotropy, context dependency, and potential toxicity present significant barriers. Overall, this review argues that while epitranscriptomics represents a compelling regulatory axis in cancer cell death, advancing the field will require integrative, high-resolution, and functionally precise approaches to move beyond correlative frameworks toward mechanistic and clinically actionable insights.
    Keywords:  Apoptosis; Epitranscriptomics; Ferroptosis; M6A RNA methylation; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s10142-026-02016-6
  31. Genetics. 2026 Aug 22. pii: iyag220. [Epub ahead of print]
    Ribosome heterogeneity provides a translational barrier against protein misfolding disease in Saccharomyces cerevisiae.
    Min Suk Jang, Sia Han, Eunsil Choi, Jihwan Hwang, Moonil Son.
      The yeast prion [PSI+] is a self-propagating amyloid of the translation termination factor Sup35p (eRF3). Among 79 ribosomal proteins in Saccharomyces cerevisiae, through a genetic screen for novel anti-prion factors, we identified RPL24B, a 60S ribosomal subunit protein, as a key determinant of prion generation. Our findings revealed that the functional distinction between the ribosomal paralogs RPL24A and RPL24B is the primary driver of ribosomal heterogeneity-based anti-prion generation. Heterogeneity establishes a critical genetic checkpoint that strictly regulates the emergence and heritable diversity of prions and their variants. We demonstrate that deleting RPL24B (rpl24bΔ) significantly increased the frequency of [PSI+] generation compared to the wild-type strain. Crucially, the resulting [PSI+] prions in the rpl24bΔ mutants exhibited distinct heritable diversity, characterized by high thermostability and exceptionally high propagon numbers. This anti-prion activity is uniquely specific to the RPL24B paralog, because deletion of its highly homologous counterpart, RPL24A, does not reproduce the effects observed in rpl24bΔ. Mechanistically, we identified valine 138 (V138) in Rpl24b as the major molecular determinant of its anti-prion generation activity. Loss of Rpl24b perturbs the cellular protein quality control landscape, leading to high accumulation of misfolded protein aggregates. This work suggests that RPL24B functions as a specialized retainer of genetic robustness, providing a translational barrier against protein misfolding diseases by filtering out robust amyloid variants.
    Keywords:  Ribosomal protein; [PSI+]; [URE3]; prion; yeast
    DOI:  https://doi.org/10.1093/genetics/iyag220
  32. Technol Cancer Res Treat. 2026 Jan-Dec;25:25 15330338261481298
    METTL3-Mediated m6A Modification of COL5A2 Inhibits Ferroptosis Through an IGF2BP3-dependent Mechanism in Gastric Cancer.
    Guo Xin, Li Shuang, Guo Yuying, Ji Lina.
      IntroductionMETTL3, the core enzyme of m6A methylation, influences gastric cancer (GC) progression, but its role in ferroptosis remains unclear. This study investigated the regulatory role of METTL3 in GC ferroptosis and its underlying mechanism via the downstream target gene collagen type V alpha 2 chain(COL5A2).MethodGC cell lines (AGS, MKN-45) and normal GES-1 cells were used. Ferroptosis was induced by erastin and RSL-3. METTL3 overexpression/knockdown models were constructed to assess ferroptosis indicators, including lipid reactive oxygen species(ROS), malondialdehyde(MDA), Fe2+, glutathione(GSH) and malignant phenotypes. m6A sites were predicted and validated by MeRIP-qPCR. m6A readers were knocked down to identify effectors, and mRNA stability was evaluated via RIP and actinomycin D assays. The focal adhesion kinase(FAK)/mitogen-activated protein kinase(MAPK)/extracellular signal-regulated kinase(ERK)pathway and ferroptosis-related proteins were detected by Western blot, with pathway involvement confirmed using the FAK inhibitor PF-573228. To validate the in vitro findings, a nude mouse xenograft tumor model was established.ResultsMETTL3 was highly expressed in GC cells and suppressed by ferroptosis inducers. METTL3 overexpression inhibited ferroptosis (reducing ROS, MDA, Fe2+, increasing GSH) and promoted proliferation and migration. COL5A2 was positively correlated with METTL3. MeRIP-qPCR confirmed that METTL3 mediates m6A modification of COL5A2's 3'-UTR. RIP and ActD assays demonstrated that the m6A reader insulin-like growth factor 2 mRNA-binding protein 3(IGF2BP3) maintains COL5A2 mRNA stability. IGF2BP3 knockdown promoted ferroptosis and apoptosis, which were reversed by COL5A2 overexpression. Furthermore, COL5A2 overexpression activated the FAK/MAPK/ERK pathway, upregulated GPX4, and inhibited ferroptosis; these effects were counteracted by the FAK inhibitor. In vivo, METTL3 overexpression promoted tumor growth, reduced 4-HNE levels, and regulated ferroptosis and FAK/MAPK/ERK pathway proteins, all of which were reversed by COL5A2 knockdown.ConclusionMETTL3 upregulates COL5A2 expression through m6A modification, with IGF2BP3 maintaining COL5A2 mRNA stability. This subsequently activates the FAK/MAPK/ERK signaling pathway, inhibits ferroptosis, and promotes GC progression. The METTL3/IGF2BP3/COL5A2 axis represents a promising therapeutic target for GC treatment.
    Keywords:  COL5A2; FAK/MAPK/ERK; IGF2BP3; METTL3; ferroptosis; gastric cancer
    DOI:  https://doi.org/10.1177/15330338261481298
  33. Epigenomics. 2026 Aug 24. 1-13
    m6A epitranscriptomic regulation in asthma: mechanisms and therapeutic prospects.
    Wufei Ye, Jingrui Ye, Bohan Wang, Yang Ruan, Yanqiu Xu, Chaofeng Zhang.
      Asthma is a heterogeneous airway disease in which chronic inflammation, epithelial barrier injury, immune-cell imbalance and airway remodeling interact to shape variable clinical phenotypes. N6-methyladenosine (m6A), the most abundant internal modification of eukaryotic mRNA, has emerged as a dynamic epitranscriptomic layer that regulates RNA splicing, export, stability, translation and decay. Recent profiling studies and mechanistic experiments indicate that m6A patterns and m6A regulators are altered in lung tissue, airway epithelial cells, airway smooth muscle cells and immune cells in asthma. These changes influence type 2 inflammation, the balance between T helper 1 (Th1) and T helper 2 (Th2) cells, the balance between T helper 17 (Th17) and regulatory T (Treg) cells, macrophage polarization, epithelial ferroptosis, ciliary function, mitochondrial stress, pollutant responses and structural remodeling. This Review synthesizes current evidence linking m6A writers, erasers and readers to asthma pathobiology, highlights context-dependent and sometimes opposing functions of key regulators such as METTL3, FTO and ALKBH5, and discusses how m6A signatures may inform biomarker discovery and therapeutic development. We also outline major translational barriers, including cell-type specificity, target validation, assay standardization and safety of pharmacologic m6A modulation.
    Keywords:  Asthma; RNA methylation; epitranscriptome; immunoregulation; m6A modification
    DOI:  https://doi.org/10.1080/17501911.2026.2721821
  34. Viruses. 2026 Aug 21. pii: 920. [Epub ahead of print]18(8):
    The L-A dsRNA Virus and Its Satellites: Totiviruses and Killers in Saccharomyces cerevisiae.
    Reed B Wickner, Herman K Edskes.
      A secreted protein toxin encoded by a satellite dsRNA-enabled dissection of the genetic control of replication and expression of a single-segment dsRNA virus, the first Totivirus, L-A. Among the then-novel findings were i. "head-full replication", ii. a supposedly forbidden "T = 2" capsid symmetry based on an asymmetric dimer, iii. a host N-acetyltransferase whose modification of the coat protein is necessary for packaging, iv. Kex1 and Kex2 pro-toxin peptidases leading to discovery of the pre-pro-insulin processing enzymes, and v. specific viral (+) strand sites/structures needed for RNA packaging and (-) strand synthesis. L-A viral (+) strands made in the particle are extruded to the cytoplasm. Those destined for translation are 5' 7meGMP-capped by a coat protein activity that steals the cap from cellular mRNAs. (+) strands destined for encapsidation in new coats are not capped. Three host-encoded anti-viral systems were found, one based on blocking translation of the viral non-polyA mRNAs (Ski2,3,8 complex), another a 5'->3' exoribonuclease specific for uncapped molecules (such as the viral (+) strands)(Ski1/Xrn1), and the third a mitochondrial nuclease released in cells undergoing meiosis/sporulation (Nuc1). All of these systems protect cells from virus-induced pathology and have clear animal homologs. The 3' polyA of yeast mRNAs is dispensable for translation in ski2Δ slh1Δ cells, and such cells are healthy unless the L-A and M dsRNAs are present, suggesting that this polyA is primarily a device allowing cells to distinguish viral and cellular mRNAs. We suggest that the ribosome-associated Ski2,3,8 proteins block 60S subunit joining on polyA- mRNAs. Recent evidence of roles for other cellular components controlling viral expression and replication suggests that yeast viruses will continue to be a fertile area for study of viral pathogenesis and host anti-viral systems.
    Keywords:  Nuc1; Ski; Totivirus; anti-virus; dsRNA virus; killer; polyA; translation control
    DOI:  https://doi.org/10.3390/v18080920
  35. Cell Rep. 2026 Aug 22. pii: S2211-1247(26)00965-4. [Epub ahead of print]45(9): 117887
    16S ribosomal RNA modification drives transcript-specific translation efficiency.
    Zachory M Park, Christina R Savage, Amanda R Decker-Farrell, Chin-Hsien Tai, Tapan K Maity, Weiming Yang, Lisa M Jenkins, Kumaran S Ramamurthi.
      Bacterial ribosomal RNAs (rRNAs) are decorated with conserved nucleotide modifications, but the functionality of these modifications is often underexplored. MraW (RsmH) is a 16S rRNA methyltransferase. Here, we report that deletion of mraW corrects a late-stage sporulation defect in Bacillus subtilis by bypassing a sporulation checkpoint. Ribosomes purified from ΔmraW cells display a ∼2-fold decrease in translation efficiency; in vivo, ΔmraW cells produced decreased levels of the sporulation checkpoint protein CmpA. Reduced production of CmpA is mediated by mRNA sequences that form a stem-loop which occludes early cmpA codons. Proteomic analysis revealed that MraW mediates production of multiple proteins, some of whose mRNA form similar structures as the cmpA transcript. We propose that MraW modification of 16S rRNA enhances translation efficiency in general, and that specific transcripts have evolved structural features that fine-tune protein levels. This type of control may be prevalent in bacteria which exhibit uncoupled transcription and translation.
    Keywords:  30S subunit; CP: microbiology; CP: molecular biology; RsmI; SpoIVA; SpoVM; elongation; initiation; stationary phase
    DOI:  https://doi.org/10.1016/j.celrep.2026.117887
  36. Pharmaceuticals (Basel). 2026 Aug 08. pii: 1250. [Epub ahead of print]19(8):
    Targeting ADAR1 in Cancer: Biology, Therapeutic Strategies, Challenges, and Limitations.
    Carolyn N Ashley, Emmanuel Broni, ChaNyah M Wood, Simon Kaja, Sean W Fanning, Scarlett Schuth, Whelton A Miller.
      Adenosine deaminase acting on RNA 1 (ADAR1) is a critical regulator of innate immune signaling and a pan-cancer therapeutic target. Through catalyzing adenosine-to-inosine (A-to-I) editing and editing-independent mechanisms, ADAR1 suppresses activation of dsRNA sensing pathways, including protein kinase R (PKR), melanoma differentiation-associated protein 5 (MDA5), and oligodenylate-synthetase (OAS) signaling, that are critical for maintaining cellular tolerance to endogenous RNAs. In a subset of tumors characterized by elevated interferon-stimulated gene (ISG) expression and dsRNA stress, this function creates a dependency on ADAR1 for survival, establishing a therapeutic vulnerability that can be exploited to induce viral mimicry in cancer cells and enhance anti-tumor immune responses. Here, we review the emerging landscape of ADAR1 modulators, organizing reported compounds into mechanistic classes including nucleoside analogs, catalytic inhibitors, Zα domain modulators, RNA substrate engagement inhibitors, indirect pathway regulators, and PROTACs. We evaluate molecules within these classes with a focus on their mechanisms of action and experimental validation. We further discuss the challenges associated with distinguishing direct inhibition of ADAR1 activity from broader effects on RNA metabolism and innate immune activation. Finally, we highlight the therapeutic potential of ADAR1 targeting defined cancer subsets and examine combination strategies that leverage ADAR1 inhibition for improved sensitivity to current cancer therapeutics. Overall, this review outlines key considerations for the development of selective therapies targeting ADAR1.
    Keywords:  ADAR1; RNA editing modulators; cancer therapeutics; small molecule inhibitors
    DOI:  https://doi.org/10.3390/ph19081250
  37. Mol Biol Rep. 2026 Aug 27. pii: 1469. [Epub ahead of print]53(1):
    tRNA-derived small RNAs in vascular smooth muscle cell phenotypic switching and vascular remodelling.
    Kun Li, Xinqiu Li.
      tRNA-derived small RNAs (tsRNAs) are noncoding RNAs generated from precursor or mature tRNAs. Basal tsRNA levels are detectable under physiological conditions, but their production increases sharply under cellular stress. tsRNAs regulate gene expression through miRNA-like targeting, translational control, and intercellular communication. In vascular remodelling disorders-including atherosclerosis (AS), aortic dissection (AD), and in-stent restenosis (ISR)-vascular smooth muscle cells (VSMCs) undergo phenotypic switching from contractile to synthetic states. Pulmonary hypertension (PH) shares similar phenotypic features, but the current evidence on the role of tsRNAs in PH remains largely predictive. Several experimentally studied tsRNAs affect VSMC phenotypic behaviour in disease- and context-dependent manners by targeting key signalling molecules, including STAT4, FMOD, FAS, and CBX3/HP1γ, with downstream consequences for contractile gene expression and proliferative behaviour. Notably, these tsRNAs act bidirectionally: 5'-tiRNA-Cys-GCA and tRF-Glu-CTC (via FMOD targeting) suppress the synthetic phenotype and neointimal formation, whereas tRF-Gln-CTG promotes it. We propose an evidence-mapped conceptual framework organized by regulatory layers-transcriptional, posttranscriptional, and chromatin-associated regulation-while acknowledging that cross-layer interactions remain to be experimentally verified. Clinically, tsRNAs hold promise as liquid biopsy biomarkers and therapeutic targets, but the current evidence is preliminary and requires validation against established biomarkers before translational application. This review synthesizes the current evidence on tsRNA biology in the context of VSMC phenotypic switching and outlines a roadmap for future research.
    Keywords:  Aortic dissection; Atherosclerosis; Biomarkers; Phenotypic switching; Vascular smooth muscle cells; tRNA-derived small RNAs
    DOI:  https://doi.org/10.1007/s11033-026-12621-0
  38. Cells. 2026 Aug 16. pii: 1467. [Epub ahead of print]15(16):
    The m6A Reader YTHDC2: Molecular Mechanisms and Regulatory Networks in Disease Pathogenesis.
    Yanying Hu, Qi Zhou, Ning Xu, Ning Du, Shuangping Yang, Shiyan Gu.
      As a key N6-methyladenosine (m6A)-binding protein, YT521-B Homology (YTH) Domain-Containing Protein 2 (YTHDC2) plays a central role in the epitranscriptomic regulatory network. This protein specifically recognizes and binds to m6A modification sites on RNA molecules through its highly conserved YTH domain. This recognition exhibits high selectivity and affinity, thereby enabling precise control over the fate of target RNAs. At the molecular level, YTHDC2 is widely involved in various stages of the RNA life cycle, including core biological processes such as RNA splicing and processing, nuclear-cytoplasmic transport, translational efficiency regulation, and RNA decay. In recent years, accumulating evidence indicates that YTHDC2 participates in a variety of pathophysiological processes in an m6A-dependent manner. However, the robustness of evidence regarding YTHDC2 is heterogeneous across disease contexts. While certain pathologies are supported by rigorous mechanistic validation, others rely primarily on expression correlations or bioinformatic analyses. This review systematically synthesizes current knowledge regarding the multifaceted roles of YTHDC2 in disease progression, prognosis, and therapy, offering a comprehensive framework to guide future investigations.
    Keywords:  N6-methyladenosine (m6A) modification; YT521-B Homology (YTH) Domain Containing 2; digestive system diseases; immune system; nervous system; reproductive system; respiratory system diseases
    DOI:  https://doi.org/10.3390/cells15161467
  39. Int J Mol Sci. 2026 Aug 19. pii: 7427. [Epub ahead of print]27(16):
    DTT-Induced Transcriptome Profiling Reveals Divergent ER Proteostasis and Stress-Adaptation Programs in CHO-S/HB8 and CHO-4BGD/DUL Producer Clones.
    Nadezhda A Orlova, Nadezhda A Potapova, Rolan R Shaifutdinov, Ivan I Vorobiev.
      Chinese hamster ovary (CHO) producer cells differ in their capacity to accommodate secretory and endoplasmic reticulum (ER) stress, but how producer and host-cell backgrounds are associated with ER-proteostasis responses remains poorly understood. We compared 24 h dithiothreitol (DTT)-induced reductive ER stress responses in two clonal producers: CHO-S-derived HB8 secreting human chorionic gonadotropin and apoptosis-resistant CHO-4BGD-derived DUL secreting a GLP-1-Fc fusion protein with similar specific productivities. Responses were analyzed by strand-specific RNA-seq, Xbp1-splicing RT-PCR, immunoblotting, functional enrichment, and curated-module analysis. Analysis of the complete three-replicate dataset identified 299 DTT-responsive genes in HB8 and 877 in DUL, demonstrating a broader transcriptional response in the DUL clone. Analysis after exclusion of the atypical HB8#3 matched pair yielded 404 and 1019 differentially expressed genes, respectively, and was used for detailed sensitivity analysis. Both producers showed ISR/ATF4/CHOP-associated transcriptional activation and Xbp1 mRNA splicing, whereas changes in total Xbp1 and Hspa5/BiP transcript abundance were limited. BiP and CHOP accumulation was detected at the protein level, while phospho-eIF2α and ATF6 responses were variable. Baseline RNA-seq data comparison revealed extensive transcriptional divergence between HB8 and DUL. HB8 showed higher expression of several classical ER folding/redox factors, whereas DUL showed higher expression of selected ISR-, quality-control- and stress-survival-associated genes. DUL additionally displayed broader vesicle/endocytic and amino-acid/glutathione-related remodeling. Thus, the producers occupy distinct ER-proteostasis states, and DUL mounts a broader, but not uniformly stronger, canonical UPR response to reductive ER stress.
    Keywords:  BiP/GRP78; CHO cells; DTT; ERAD; ISR; PERK; RNA-seq; XBP1 splicing; apoptosis-resistant CHO; endoplasmic reticulum stress; secretory pathway; unfolded protein response
    DOI:  https://doi.org/10.3390/ijms27167427
  40. Plant Mol Biol. 2026 Aug 24. pii: 83. [Epub ahead of print]116(5):
    The AtRNC1-AtWTF1 protein complex is essential for chloroplast group Ⅱ intron splicing, ribosome biogenesis, and embryo development in Arabidopsis.
    Yichen Zhang, Xinyun Xu, Yajuan Li, Siwen Wei, Jiayi Shen, Qing-Bo Yu, Yong-Lan Cui.
      The splicing of group Ⅱ introns in chloroplasts is essential for photosynthesis and plant development and relies on a series of nucleus-encoded RNA-binding proteins. Here, we demonstrate that two Arabidopsis proteins, ribonuclease Ⅲ-domain protein AtRNC1 and the Plant organelle RNA recognition (PORR) protein AtWTF1, are essential for chloroplast function. Null mutants of AtRNC1 or AtWTF1 are embryo lethal. We rescued the null mutant by expressing wild-type AtRNC1 under the control of the seed-specific ABSCISIC ACID-INSENSITIVE3 (ABI3) promoter. We also created atrnc1 knockdown plants using artificial-microRNA (amiRNA). Both the rescued and knockdown atrnc1 plants exhibit chlorotic phenotype. Similarly, AtWTF1 hypomorphic mutants display variegated phenotypes. Both proteins are chloroplast-localized, with AtRNC1 residing in the stroma and AtWTF1 in both the stroma and thylakoids. Molecular phenotyping established that AtRNC1 and AtWTF1 are required for the efficient splicing of a specific, overlapping set of chloroplast group Ⅱ introns, including those in petB, petD, rpl2, rps12, and tRNAs. RNA immunoprecipitation confirmed the association of both proteins with their target introns in vivo, indicating direct roles in splicing. The knockdown of AtRNC1 or AtWTF1 in Arabidopsis impairs the chloroplast ribosome accumulation and accordingly reduced the efficiency of mRNA translation. Notably, protein interaction assays, including yeast two-hybrid, luciferase complementation image, and IP-MS indicate that AtRNC1 and AtWTF1 associate with each other, implying their cooperative function in a splicing complex. These findings establish AtRNC1 and AtWTF1 as key components of the chloroplast RNA splicing machinery, essential for the maturation of plastid transcripts and overall chloroplast homeostasis in Arabidopsis.
    Keywords:   Arabidopsis thaliana ; AtRNC1; AtWTF1; Chloroplast translation; RNA splicing; Ribosome biogenesis
    DOI:  https://doi.org/10.1007/s11103-026-01756-0
  41. J Plant Physiol. 2026 Aug 26. pii: S0176-1617(26)00181-1. [Epub ahead of print]325 154868
    Intron retention as a hub for splicing regulation in plant environmental adaptation and developmental programming.
    Weibo Xu, Meng Wang, Like Liu.
      Alternative splicing (AS) greatly expands transcriptome and proteome diversity in eukaryotes. Intron retention (IR) is the predominant AS type in plants, with critical roles in environmental adaptation and developmental control. Long viewed as splicing noise, IR is now established as a precisely regulated mechanism that modulates RNA stability, translation, subcellular localization, and protein function. Here, we review recent advances in plant IR research, covering technical progress in accurate IR identification using long-read and single-cell sequencing, cis- and trans-regulatory mechanisms, epigenetic coupling with transcription, and signal integration pathways. We highlight key functions of IR in flowering time regulation and stress responses, including the IR-nonsense-mediated mRNA decay (NMD) axis, functional protein isoforms, and nuclear transcript reservoirs for rapid stress memory. Finally, we discuss unresolved questions and future directions toward single-cell spatiotemporal dynamics, phase separation, and synthetic IR modules for crop improvement. This review provides an integrated framework for understanding IR as a central regulatory hub in plant post-transcriptional control.
    Keywords:  Alternative splicing; Environmental stress adaptation; Intron retention; Plant development; Post-transcriptional regulation
    DOI:  https://doi.org/10.1016/j.jplph.2026.154868
  42. EMBO J. 2026 Aug 22.
    From water to land: evolution of tRNA gene repertoires in photosynthetic organisms.
    Guillaume Hummel, David Pflieger, Alexandre Berr, Laurence Drouard.
      Photosynthetic eukaryotes have undergone evolutionary shifts from aquatic to terrestrial habitats, accompanied by changes in genome organization and gene regulation. Yet, the evolution of transfer RNA (tRNA) gene repertoires has received limited attention despite their central role in translation. Here, we review how tRNA gene content, structure, and genomic organization diversified across photosynthetic lineages, mainly Archaeplastida, and how changes relate to evolutionary transitions. We show that tRNA gene repertoires are shaped by ecological transitions, genome architecture, and translational demands. We highlight terrestrialization as a shift in tRNA evolution, marked by loss of selenocysteine and its dedicated tRNA, and changes in intron prevalence and structure. Copy number variation correlates with codon usage and amino acid composition, and in angiosperms, nuclear tRNA genes display reinforced cis-regulatory elements consistent with increased translational demands. We show that plant tRNA genes exhibit evenly dispersed arrangements, except in some algae enriched in clustered configurations. Together, these observations support a model in which tRNA gene repertoires are drivers of genome evolution, integrating translational demand, genomic organization, and ecological adaptation across photosynthetic lineages.
    DOI:  https://doi.org/10.1038/s44318-026-00904-y
  43. Bone. 2026 Aug 26. pii: S8756-3282(26)00296-6. [Epub ahead of print] 118070
    ZCCHC4-mediated m6A methylation regulates the UHRF1/CDO1 axis to inhibit ferroptosis and promote osteosarcoma malignant progression.
    Kai Song, Ju Liu, Bowen Han, Rui Liu, Huazhang Zhong, Dasheng Tian.
       BACKGROUND: Osteosarcoma (OS) represents a common primary malignant bone tumor associated with unfavorable clinical outcomes. Growing evidence underscores the crucial involvement of N6-methyladenosine (m6A) modifications in tumor development, but the specific mechanisms underlying the m6A regulatory network in OS remain to be elucidated.
    METHODS: Potential key target genes in OS were identified through bioinformatic analyses, followed by the characterization of m6A-related regulatory proteins, specifically, writer and reader proteins, which showed significant associations with these targets. To elucidate the mechanistic role of m6A methylation in regulating UHRF1 expression, a series of in vitro assays were conducted. These included RNA pull-down, MeRIP-PCR, dot blot, dual-luciferase reporter assays, and RNA stability assays, which collectively confirmed the interaction between m6A regulatory proteins and UHRF1 mRNA. For functional investigations, OS cell lines (U2OS, Saos2, and 143B) with gene silencing or overexpression were established, and the role of UHRF1 in cellular proliferation, migration, and invasion was assessed using CCK-8 assays, Transwell migration and invasion assays, flow cytometry, and wound healing assays. In addition, GSH/GSSG ratio, Fe2+ concentration, and ROS levels were measured using commercial assay kits to explore ferroptosis-related functional mechanisms. To validate the in vivo relevance of our findings, a xenograft mouse model was established. Finally, functional rescue experiments were performed to mechanistically confirm the critical role of the ZCCHC4-UHRF1-CDO1 regulatory axis in OS progression.
    RESULTS: ZCCHC4, functioning as an m6A methyltransferase, enhances the stability of UHRF1 mRNA by catalyzing its m6A modification, thereby promoting increased expression of UHRF1. In parallel, IGF2BP3, an established m6A reader protein, specifically recognizes and binds to the m6A-modified sites on UHRF1 mRNA, further stabilizing the transcript and modulating its downstream biological functions. METTL3/METTL14 knockdown experiments ruled out the contribution of classical m6A methyltransferases, confirming that ZCCHC4 is the primary methyltransferase for UHRF1. Dual-luciferase assays and bisulfite sequencing revealed that UHRF1 suppresses CDO1 transcription by inducing high methylation of its promoter, thereby reducing ROS/Fe2+ levels and increasing GSH, which in turn blocks ferroptosis. In U2OS, Saos2, and 143B cells, silencing UHRF1 or ZCCHC4 inhibited proliferation, migration, and invasion while activating ferroptosis. Overexpression of UHRF1 had the opposite effect. In vivo models confirmed that UHRF1 silencing inhibited tumor growth. Furthermore, UHRF1 overexpression partially reversed the phenotypes induced by ZCCHC4 knockdown.
    CONCLUSION: In summary, this study reveals for the first time the complete molecular mechanism by which ZCCHC4-mediated UHRF1 m6A methylation promotes OS progression through epigenetic suppression of CDO1 transcription and inhibition of ferroptosis. This regulatory axis (ZCCHC4-IGF2BP3-UHRF1-CDO1-ferroptosis) provides multiple therapeutic targets for OS and lays a solid foundation for the future development of anticancer strategies based on the regulation of ferroptosis, while also offering a promising pathway for clinical translation.
    Keywords:  Ferroptosis; Osteosarcoma; UHRF1; m6A methylation
    DOI:  https://doi.org/10.1016/j.bone.2026.118070
  44. EMBO Rep. 2026 Aug 22.
    The ER-Golgi intermediate compartment: a central hub integrating membrane trafficking and stress responses.
    Yingying Guo, Jianfei Zheng, Lei Liu, Shulin Li, Min Zhang, Liang Ge.
      The endoplasmic reticulum-Golgi intermediate compartment (ERGIC) is a dynamic membrane system at the ER-Golgi interface, traditionally viewed as a transient station for COPII- and COPI-dependent trafficking. Emerging evidence redefines the ERGIC as a stress-responsive regulatory hub that integrates membrane trafficking with cellular adaptation. In addition to coordinating bidirectional transport and cargo sorting, the ERGIC actively participates in protein quality control during ER stress and remodels trafficking flux under perturbations. It serves as a platform linking secretory pathways to stress signaling, contributing to autophagosome biogenesis, facilitating unconventional protein secretion under stress conditions, and modulating innate immune responses, including STING activation. The ERGIC is also co-opted by pathogens such as coronaviruses, underscoring its role at the interface of membrane remodeling and host defense. These functions position the ERGIC as a central integrator of trafficking dynamics and stress responses, whose structural plasticity enables rapid adaptation to physiological and pathological challenges.
    DOI:  https://doi.org/10.1038/s44319-026-00908-z
  45. Front Immunol. 2026 ;17 1911067
    Crosstalk between m6A modification and metabolic reprogramming in colorectal cancer: from the immune microenvironment to clinical applications.
    Liang Zhao, Zhitao Yin, Chenchun Ji, Yan Wu, Hongjian Gao, Hexue Yuan.
      N6-methyladenosine (m6A) modification is the most common epigenetic alteration in eukaryotic mRNA, significantly impacting metabolic reprogramming and the tumor microenvironment (TME) of colorectal cancer (CRC) by dynamically regulating RNA metabolic processes. Recent studies indicate that m6A modification interacts with CRC metabolic reprogramming, fostering an immunosuppressive TME. Specifically, m6A modification promotes CRC progression by regulating glucose, lipid, and amino acid metabolism while inhibiting the activity of antitumor immune cells (such as T cells, natural killer cells, and macrophages) and activating tumor immunosuppressive cells (including tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, tumor-associated neutrophils, and cancer-associated fibroblasts). This article systematically reviews the molecular mechanisms through which m6A modification drives the malignant progression of CRC via metabolic regulation, elucidates the metabolic network involving m6A modification and its role in shaping TME, and discusses the clinical potential of targeting m6A modification and/or metabolic pathways, offering novel research avenues for CRC treatment.
    Keywords:  CRC; TME; gut microbiota; m6A; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fimmu.2026.1911067
  46. MedComm (2020). 2026 Sep;7(9): e70938
    RNA-Binding Proteins: Function, Biological Mechanisms, and Therapeutic Opportunities.
    Ling Li, Xiuli Yan, Qing Ji, Hui Zhang.
      RNA-binding proteins (RBPs) are central regulators of post‑transcriptional gene expression, controlling RNA stability, localization, translation, and alternative splicing. Their functions arise not only from intrinsic RNA-binding domains but also from dynamic interactions with noncoding RNAs, metabolites, cofactors, and other RBPs. Here, we summarize the structural diversity and core biological activities of canonical and noncanonical RBPs, and delineate how competitive and cooperative regulatory networks dictate RBP function in disease, with an emphasis on cancer. Competitive mechanisms, including lncRNA-mediated sequestration, antagonistic crosstalk between miRNAs and RBPs, and competition among RBPs for shared substrates, can redirect RNA fate. In contrast, cooperative mechanisms assemble multimolecular ribonucleoprotein complexes that reinforce oncogenic or tumor-suppressive programs. Dysregulation of these networks promotes proliferation, metastasis, immune evasion, and therapy resistance. We also review emerging therapeutic strategies that target RBP-centered regulatory circuits, including antisense oligonucleotides, small molecules, protein degraders, and natural products, and we evaluate representative preclinical studies and clinical trials. By integrating mechanistic principles with translational evidence, this review provides a network-based framework for exploiting RBPs as therapeutic vulnerabilities and for advancing next-generation precision oncology.
    Keywords:  RBP interactome; RNA‐binding proteins; post‐transcriptional gene regulation; precision oncology; regulatory networks; targeted therapy
    DOI:  https://doi.org/10.1002/mco2.70938
  47. Med Oncol. 2026 Aug 24. pii: 254. [Epub ahead of print]43(10):
    Targeting endoplasmic reticulum stress to attenuate cisplatin resistance in non-small cell lung cancer.
    Semahat Celikten, Zafer Yildirim, Sevim Aydemir, Busra Bara, Eda Dogan, Zuhal Eroglu, Vildan Bozok.
      Cisplatin-based chemotherapy remains a cornerstone of treatment for advanced non-small cell lung cancer (NSCLC); however, the emergence of chemoresistance severely limits its clinical efficacy. Endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR) have been implicated in cancer cell survival and therapy resistance, highlighting modulation of this signalling as a potential therapeutic strategy. In this study, we investigated whether pharmacological induction of endoplasmic reticulum stress via sarco/endoplasmic reticulum Ca²⁺-ATPase (SERCA) inhibition could attenuate cisplatin resistance in NSCLC. Using parental and cisplatin-resistant cell lines, we demonstrate that thapsigargin induces transcriptional responses consistent with endoplasmic reticulum stress, characterised by dynamic regulation of GRP78, PERK, XBP1, and ATF4 mRNA expression. Notably, thapsigargin pre-treatment significantly reduced cisplatin IC₅₀ values and decreased resistance indices in resistant cells, indicating attenuation of the resistant phenotype. In addition, SERCA inhibition enhanced apoptotic cell death in selected models and markedly suppressed clonogenic survival and migratory capacity across all cell lines examined. Distinct UPR-related transcriptional patterns were observed between parental and resistant cells, suggesting adaptive remodelling of ER stress signalling during acquisition of cisplatin resistance. Collectively, these findings identify ER calcium homeostasis as a modifiable determinant of platinum responsiveness and support targeting ER stress pathways as a potential adjunct strategy to improve therapeutic efficacy in chemoresistant NSCLC.
    Keywords:  ATF4; Cisplatin resistance; Endoplasmic reticulum stress; GRP78; Non-small cell lung cancer; PERK signalling; Thapsigargin; XBP1
    DOI:  https://doi.org/10.1007/s12032-026-03369-5
  48. Pharmacol Ther. 2026 Aug 28. pii: S0163-7258(26)00135-X. [Epub ahead of print] 109108
    Clusterin as a therapeutic agent: Bridging the gap in brain and eye research.
    Bushra Zaman, Avinash Soundararajan, Padmanabhan P Pattabiraman, Abdelrahman Y Fouda.
      Clusterin (CLU) is a multifunctional secreted glycoprotein that is widely expressed in human tissues and body fluids. It plays critical roles in maintaining tissue homeostasis, regulating inflammation, modulating immune responses, and promoting cellular survival in both the brain and the eye. The CLU gene undergoes alternative splicing, yielding protein isoforms with distinct, and sometimes opposing, functions within a single disease condition. While secreted CLU (sCLU) is generally associated with cytoprotection, regulation of complement activation, protein chaperoning, and resolution of inflammation, the nuclear CLU (nCLU) isoform have been implicated in cell stress responses, apoptosis, and disease progression. Understanding these isoform-specific functions is essential for interpreting the diverse and sometimes contradictory roles of CLU across disease states. In this review, we discuss endogenous CLU expression, alternative splicing, and the resulting functions of its different isoforms. In addition to its inherent physiological role, we review recent research on exogenous CLU administration in the eye and brain. We identify knowledge gaps that need to be addressed before CLU is developed as a therapeutic agent. To help with the identification of future drug targets, we also summarize common CLU mechanisms in the brain and eye. By combining and contrasting knowledge from these two interconnected organs, we identify convergent CLU-regulated pathways and therapeutic opportunities, providing a comprehensive guide to future mechanistic studies, biomarker development, and CLU-based drug discovery. Therefore, the summaries in this review make it a highly relevant reference for CLU translational research and drug discovery across multiple brain and eye disorders.
    Keywords:  Apolipoprotein J; Brain; Clusterin; Drug development; Eye; Isoforms; Therapeutic
    DOI:  https://doi.org/10.1016/j.pharmthera.2026.109108
  49. Int J Mol Sci. 2026 Aug 17. pii: 7340. [Epub ahead of print]27(16):
    A Stage-Dependent Translational Signature in Peripheral Blood Mononuclear Cells from Clinically Isolated Syndrome to Relapsing-Remitting Multiple Sclerosis: An Exploratory Cross-Sectional Study.
    Simone D'Angiolini, Aurelio Minuti.
      Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system characterized by inflammatory demyelination, neurodegeneration, and progressive disability. Clinically isolated syndrome (CIS) often represents the first overt presentation of MS. We performed an exploratory cross-sectional transcriptomic investigation of peripheral blood mononuclear cells (PBMCs) from healthy controls (HC, n = 40), CIS patients (n = 49), and Relapsing-Remitting MS (RRMS, n = 53) patients using the ArrayExpress dataset E-MTAB-11415. Differential expression analysis was performed using limma, adjusting for age and sex. Functional enrichment and network analyses were conducted using clusterProfiler, STRING, and Cytoscape. Although Principal Component Analysis (PCA) showed partial overlap among groups, pathway-level analyses revealed coherent alterations in translation, ribosome biology, mitochondrial protein synthesis, and stress-response regulation. In CIS compared with HC, cytoplasmic and mitochondrial ribosomal genes were predominantly downregulated, suggesting reduced translational capacity in PBMCs. This was accompanied by altered expression of translation-initiation and transcriptional regulators, whereas genes involved in stress-adaptive translational control, including GCN1, YARS1, QARS1, and SIL1, were selectively upregulated. Conversely, RRMS compared with CIS showed upregulation of ribosome-related and biosynthetic programs. Overall, these findings suggest that CIS may be characterized by peripheral translational restraint and adaptive stress response activation, whereas RRMS progression is associated with biosynthetic reactivation.
    Keywords:  PBMCs; clinically isolated syndrome; multiple sclerosis; relapsing-remitting multiple sclerosis; ribosome; transcriptomics; translation
    DOI:  https://doi.org/10.3390/ijms27167340
  50. J Cell Biol. 2026 Oct 05. pii: e202512059. [Epub ahead of print]225(10):
    Cell cycle-dependent translation-mediated turnover of the long noncoding RNA Malat1.
    Leah M Plasek-Hegde, Yeolhoe Kim, Rahul V Gupta, Emily A Dangelmaier, Sigrid Nachtergaele, Nadya Dimitrova.
      Increased abundance of the nuclear long noncoding RNA (lncRNA) Malat1 drives metastatic progression and is a strong predictor of poor patient prognosis. Although the mechanism that stabilizes Malat1 through processing of its 3' terminus is well-characterized, the pathways governing its turnover remain poorly understood. Here, we show that upon exit from mitosis, Malat1 localizes to the cytoplasm, where it is degraded during early G1, resetting its abundance at the start of each cell cycle. Mechanistically, we demonstrate that Malat1 turnover is mediated by a translation- and Smg1-dependent decay pathway and triggered by redundant elements. Importantly, failure to reset Malat1 levels in early G1, due to decay inhibition or in the absence of progression through mitosis, results in Malat1 accumulation. These findings uncover a cell cycle-dependent mechanism that harnesses the translation machinery to regulate Malat1 abundance and identify cancer cell dormancy as a potential mechanism underlying the widespread overexpression of Malat1 in cancer.
    DOI:  https://doi.org/10.1083/jcb.202512059
  51. Sci Adv. 2026 Aug 28. 12(35): eaec9028
    Muscular dystrophy-associated lamin variants disrupt cellular organization through a nucleolar-ribosomal axis.
    Xiangyi Ding, Sweta Kumari, Ellen F Gregory, Daniel A Starr, G W Gant Luxton.
      Emery-Dreifuss muscular dystrophy (EDMD) arises from mutations in nuclear lamins or emerin. Current pathological models emphasize defective nuclear mechanics and transcriptional regulation, yet these mechanisms cannot explain how lamina defects propagate across the cell to produce the complex pathology of laminopathies. Here, we reveal an emerging pathway linking nuclear lamina dysfunction to cytoplasmic reorganization. Using Caenorhabditis elegans EDMD models, we show that disease-linked lamin variants reduce cytoplasmic mesoscale crowding, increase molecular diffusivity, and disrupt nuclear positioning and endoplasmic reticulum architecture, which mirror phenotypes caused by ribosome depletion. Lamin dysfunction also lowers nucleolar fibrillarin levels and ribosome abundance, revealing a nucleolar-ribosomal axis that transmits nuclear defects to the cytoplasm. Loss of the redundant LEM-domain proteins emr-1 and lem-2 phenocopied lamin mutants, indicating that cytoplasmic disorganization is a shared hallmark of EDMD. These findings connect nuclear architecture to whole-cell biophysics and suggest therapeutic strategies aimed at restoring ribosome function.
    DOI:  https://doi.org/10.1126/sciadv.aec9028
  52. Mol Cancer. 2026 Aug 14. pii: 205. [Epub ahead of print]25(1):
    Programmable ZBTB7A RNA N6-methyladenosine site-specific demethylation suppresses colorectal cancer liver metastasis.
    Xuena Chen, Shuo Zhao, Bochen Liu, Yujia Fan, Huanlu Qiu, Lingtong Ren, Xinrui Zhang, Shurui Yan, Yachun An, Shirong Li, Jie An, Jinshen Wang, Huili Hu.
      Colorectal cancer liver metastasis (CRLM) is the primary cause of CRC-related mortality, with inevitable chemoresistance to targeted therapies and immunotherapy. N6-methyladenosine (m6A), as a crucial epigenetic regulator of gene expression and cellular physiology, involved in the pathogenesis of CRLM. Precise manipulation of m6A modifications could offer a non-pharmacological precision treatment for many diseases. However, the precise editing of m6A modification in regulating CRLM progression remains elusive. Here we integrated multi-omics and identified zinc finger and BTB domain-containing 7A (ZBTB7A) as an m6A-modified transcription factor that promoted CRLM. Mechanistically, METTL3-mediated m6A modification of ZBTB7A facilitated recognition by the m6A reader YTHDF1/3 complex, enhancing its translation and expression. This m6A-dependent regulation promoted CRLM progression via activation of the ARHGAP26/Rho GTPase signaling axis. Notably, we applied a targeted RNA m6A erasure (TRME) system to achieve site-specific demethylation at a single site (m6A_site_411666) within ZBTB7A mRNA, without perturbing m6A abundance. Temporal demethylation at this site is sufficient to inhibit the CRC cell migration. This study unveils the critical role of the METTL3/ZBTB7A/ARHGAP26 axis in the process of m6A-mediated CRLM and positions m6A precise editing as a promising therapy in the preclinical treatment of CRLM.
    Keywords:   ZBTB7A ; A targeted RNA m6A erasure (TRME); CRLM; m6A precise editing
    DOI:  https://doi.org/10.1186/s12943-026-02772-w
  53. Int J Mol Sci. 2026 Aug 16. pii: 7313. [Epub ahead of print]27(16):
    Epigenetic Control of Stress-Induced Depression: Emerging Roles of HDAC3 and HDAC6.
    Arathy S Mohan, Narayanan Jayasankar, Vivekanand Ankush Kashid, Ravish J Patel, Bhupendra Prajapati.
      Major depressive disorder (MDD) is a heterogeneous psychiatric disorder characterized by impaired mood, neuroplasticity, neuroinflammation, and dysregulated stress response systems. Chronic stress can induce epigenetic changes leading to depression. Evidence suggests that histone acetylation and deacetylation are epigenetic processes involved in changes in gene expression. Histone deacetylases (HDACs) modulate chromatin structure and transcription, and their dysregulation is associated with stress susceptibility, decreased brain-derived neurotrophic factor (BDNF) signaling, impaired synaptic plasticity, and inflammatory activation. HDAC isoforms HDAC3 and HDAC6 have emerged as epigenetic regulators in stress-induced depression. HDAC3 is a transcriptional regulator involved in neuroplasticity-related gene expression, inflammatory signaling, and glucocorticoid receptor-mediated stress responses. In contrast, HDAC6 is cytoplasmic and regulates non-histone substrates involved in microtubule dynamics, synaptic function, protein trafficking, and the regulation of the hypothalamic-pituitary-adrenal axis (HPA axis). Preclinical studies show that HDAC3 or HDAC6 inhibition can exert antidepressant-like effects by promoting neuroplasticity, reducing neuroinflammation, and restoring stress-related signaling. Dual targeting is an interesting therapeutic approach because both regulate complementary mechanisms. However, clinical translation is limited by poor blood-brain barrier penetration, systemic toxicity, insufficient isoform selectivity, and a lack of clinical evidence. This review summarizes the roles and mechanisms of HDAC3 and HDAC6, the rationale for dual targeting, translational limitations, and future therapeutic perspectives.
    Keywords:  GR signaling; HDAC3; HDAC6; antidepressant therapy; epigenetics; major depressive disorder; neuroinflammation; neuroplasticity; stress response
    DOI:  https://doi.org/10.3390/ijms27167313
  54. PLoS Biol. 2026 Aug;24(8): e3003954
    Tcf15 promotes an open nucleolar chromatin state to safeguard ribosome biogenesis and genome stability in mouse embryonic stem cells.
    Yu-Ping Dong, Yi-Min Chen, Min Tang, Hu Zhou, Lin Wang, Ping Zheng.
      Embryonic stem cells (ESCs) exhibit a hyperactive chromatin state at ribosomal RNA (rRNA) genes, which not only plays roles in active rRNA synthesis and ribosome biogenesis (RiBi), but also links to genome architecture. However, how this active chromatin state is maintained in ESCs remains poorly understood. Here, we identify Tcf15, a mouse ESC-specific factor, as a novel regulator of ribosomal DNA (rDNA) chromatin state. Tcf15 localizes to the nucleolus, binds the coding region of rRNA genes, and independently recruits epigenetic modifiers-either Tet2 or Rbbp5 (a core component of H3K4 methyltransferases)-to promote an active chromatin configuration. Depletion of Tcf15 increases DNA methylation and H3K27me3 levels at rDNA. Intriguingly, the Tcf15-Rbbp5 axis ensures precursor rRNA transcription and RiBi, whereas the Tcf15-Tet2 axis is not involved in rRNA synthesis. Ribosome profiling further revealed compromised translation of a subset of mRNAs involved in DNA replication, damage response, and repair. Consequently, Tcf15- or Rbbp5-deficient ESCs exhibit severe genomic instability. Our findings add a new regulatory layer of chromatin state in rDNA of stem cells, and reveal a previously unrecognized phenotypic consequence of defective RiBi in ESCs.
    DOI:  https://doi.org/10.1371/journal.pbio.3003954
  55. Biochim Biophys Acta Mol Basis Dis. 2026 Aug 24. pii: S0925-4439(26)00296-6. [Epub ahead of print]1873(1): 168430
    EIF2AK2 inhibits type I interferon production by inhibiting RIG-I activation and disrupting mitochondria function via recruiting VAMP8 and p-MLKL.
    Qin Chen, Jingyi Wu, Fangbin Huang, Ke Shen, Wenli Zhan, Qingliang Zheng.
      Type I interferons (IFN-I) are central to antiviral immunity, but their excessive or sustained production can result in immunopathological damage. RIG-I-like receptor (RLR) signaling is pivotal in regulating RNA virus-induced IFN-I responses and requires precise modulation to maintain immune homeostasis. Here, we report that viral infection induced elevated expression of Eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2), which is an interferon-stimulated gene (ISG) with unclear role in the innate immunity. Using EIF2AK2-deficient mice and cells, we demonstrated that the loss of EIF2AK2 specifically enhances RNA virus-induced IFN-I production in macrophages and suppresses the replication of RNA virus vesicular stomatitis virus (VSV), and that this function is tightly associated with the N-terminal dsRNA binding domain of EIF2AK2. Mechanistically, EIF2AK2 competes with RIG-I for binding viral RNA, thereby inhibiting RIG-I activation. In addition, EIF2AK2 promotes the translocation of p-MLKL to mitochondria via recruiting VAMP8, leading to disruption of mitochondrial membrane potential and dysfunction of MAVS, ultimately inhibiting IFN-I production. These findings identify EIF2AK2 as a critical negative regulator of RLR-mediated innate immune response to RNA viruses via dual inhibitory mechanisms, and suggest its potential as a therapeutic target for controlling dysregulated IFN-I responses.
    Keywords:  EIF2AK2; Negative regulator; RIG-I; Type I interferons; VAMP8
    DOI:  https://doi.org/10.1016/j.bbadis.2026.168430
  56. Anticancer Agents Med Chem. 2026 Aug 04.
    S4 Induces Apoptosis, Cell Cycle Arrest, and Metabolic Alterations in Breast Cancer Cells.
    Mervenur Yavuz, Turan Demircan.
       INTRODUCTION: Breast cancer (BC) remains a primary driver of cancer-related mortality globally, necessitating the identification of novel molecular targets. While androgen receptor (AR) signaling is a recognized modulator of breast oncology, the therapeutic efficacy of selective androgen receptor modulators (SARMs), particularly S4 (Andarine), remains poorly characterized in this context.
    METHODS: The anti-cancer activity of S4 was investigated across Estrogen Receptor-positive (MCF-7) and Triple- Negative (MDA-MB-231) models. Cellular viability, clonogenicity, and migratory capacity were assessed, alongside flow cytometric analysis of apoptosis and cell cycle distribution. Mechanistic insights were derived from quantitative gene expression profiling and untargeted LC-MS-based metabolomics.
    RESULTS: S4 treatment induced a significant, dose-dependent reduction in cellular viability, suppressed clonogenicity and migration, and promoted apoptosis and cell cycle arrest, with MCF-7 cells exhibiting S-phase arrest and MDA-MB-231 cells exhibiting G0/G1-S arrest. Gene expression analysis revealed modulation of genes associated with apoptosis, stress response, and cell-cycle regulation, supporting the anti-cancer effects of S4. Metabolomic analysis further demonstrated that S4 exposure leads to marked remodeling of metabolic pathways associated with amino acid turnover, nucleotide homeostasis, lipid metabolism, and cofactor utilization.
    DISCUSSION: These alterations point to a coordinated yet context-dependent metabolic response, characterized by shared core changes alongside distinct subtype-specific adaptations. Our findings suggest that S4 treatment is associated with significant alterations in breast cancer growth and metabolic pathways.
    CONCLUSION: The subtype-specific metabolic rewiring suggests that S4 exploits unique metabolic vulnerabilities, supporting further investigation of SARMs in breast cancer models.
    Keywords:  Breast cancer; andarine; apoptosis; cell-cycle arrest; metabolomics; selective androgen receptor modulator
    DOI:  https://doi.org/10.2174/0118715206494213260708101802
  57. Int J Mol Sci. 2026 Aug 21. pii: 7481. [Epub ahead of print]27(16):
    Tyrosine Supplementation Rescues a Growth Defect in a Humanized S. cerevisiae Model of YARS1 Associated with CMT-DI.
    Nancy Sun, Tristan N Samuels, Kyle Hoffman, Ridhwan Busari, Zain Nasir, Nicole Girard, Noah M Reynolds, Ilka U Heinemann.
      Dominant pathogenic mutations in tyrosyl-tRNA synthetase (YARS1) are associated with Charcot-Marie-Tooth disease (CMT), a progressive peripheral neuropathy for which no disease-modifying therapies currently exist. While recent advances in amino acid supplementation therapies suggest potential benefit for recessive aminoacyl-tRNA synthetase disorders, their applicability to dominant YARS1-associated neuropathies remains unclear. Here, we investigated the pathogenic mechanisms underlying the dominant YARS1 variants G41R, D81I, and E196Q. Using biochemical and functional analyses, we identified increased structural rigidity for G41R and E196Q proteins, while D81I is more susceptible to tryptic digestion. Furthermore, expression of the YARS1 variants in a humanized yeast model produced a dominant negative growth defect that is exacerbated at elevated temperatures, supporting disruption of canonical YARS1 function as a contributor to disease pathogenesis. Notably, tyrosine supplementation significantly rescued the observed growth defects across variants. These findings demonstrate that impaired tyrosine utilization contributes to the pathogenic effects of dominant YARS1 variants and provide proof-of-concept evidence that tyrosine supplementation may represent a potential therapeutic strategy for patients with YARS1-associated CMT.
    Keywords:  ARS disease; amino acid supplementation; aminoacyl-tRNA synthetase; transfer RNA
    DOI:  https://doi.org/10.3390/ijms27167481
  58. Nat Cell Biol. 2026 Aug 25.
    The proportional scaling of mRNA and ribosome concentrations controls eukaryotic cell growth.
    Xin Gao, Michael Lanz, Rosslyn Grosely, Jonas Cremer, Joseph Puglisi, Jan M Skotheim.
      Cell growth underlies nearly all eukaryotic physiology, yet its quantitative principles remain unclear. Here, using single-molecule ribosome tracking, spike-in RNA sequencing and quantitative proteomics across 15 nutrient-limited conditions in budding yeast, we define how growth is controlled in the budding yeast Saccharomyces cerevisiae. Ribosome concentration scales linearly with growth rate, while peptide elongation speed remains constant at approximately nine amino acids per second. While elongation is not a regulatory lever, total mRNA concentration increases proportionally with ribosomes to accelerate growth. A simple kinetic model of mRNA-ribosome binding accurately predicts the fraction of active ribosomes, growth rate and responses to transcriptional or size perturbations. Consistent with this model, transient inhibition of mRNA degradation boosts growth by elevating mRNA concentration. These results reveal that eukaryotic cells accelerate proliferation primarily by proportionally scaling mRNA and ribosome abundance, establishing a quantitative framework for understanding eukaryotic biosynthesis.
    DOI:  https://doi.org/10.1038/s41556-026-02045-0
  59. NAR Cancer. 2026 Sep;8(3): zcag019
    SNHG family lncRNAs promote Ewing sarcoma cell fitness through intronic snoRNA-guided rRNA modifications.
    Marcela Briones-Martin-Del-Campo, Alex G Lee, Truc Dinh, Virginie Marchand, Yuri Motorin, Marta Román, Qiuli Bi, Stanley G Leung, Max A Horlbeck, Leanne C Sayles, Bo Kyung Alex Seong, Luke Gilbert, Kimberly Stegmaier, E Alejandro Sweet-Cordero.
      Over 90% of Ewing sarcomas (EWS) are driven by the EWS-FLI1 fusion oncoprotein. EWS-FLI1 acts as a pioneer transcription factor, altering the expression of hundreds of genes including many long non-coding RNAs (lncRNAs). The role of these lncRNAs in the oncogenesis of EWS is mostly unknown. We developed a CRISPR interference (CRISPRi) strategy to knock down expression of lncRNA loci expressed in EWS and evaluate their effect on proliferation in vitro and tumor growth in vivo. While most lncRNA knockdown had minimal effect on cell proliferation, selective inhibition of SNHG1, SNHG12, and SNHG30 significantly reduced both proliferation of Ewing cells in vitro and the growth of Ewing tumors in vivo. These results were validated by individual knockdown followed by RNA-seq to assess their functional impact. We observed a decrease in post-transcriptional modifications (2'-O-methylation and pseudouridylation) at specific rRNA positions known to be guided by snoRNAs encoded in SNHG1 and SNHG12. Collectively, we demonstrate that expression of SNHG1, SNHG12, and SNHG30 in EWS cells contributes to the maintenance of cancer cell fitness via their role in intron-processed snoRNA genes. Thus, post-transcriptional regulation of rRNA may be a previously underappreciated consequence of EWS-FLI1 expression.
    DOI:  https://doi.org/10.1093/narcan/zcag019
  60. Mol Biol Rep. 2026 Aug 25. pii: 1456. [Epub ahead of print]53(1):
    The dual role of AMPK in cancer metabolic reprogramming.
    Xueqing Han, Weiming Zhao.
      Metabolic dysregulation is a core hallmark of tumor cells, which reshapes energy metabolism patterns to meet the demands of rapid proliferation, invasion, metastasis, and drug resistance. AMP‑activated protein kinase (AMPK), as a central regulator of cellular energy homeostasis, senses changes in the intracellular AMP/ATP ratio and extensively participates in the regulation of glucose metabolism, lipid metabolism, amino acid metabolism, and autophagy. In the field of oncology, the role of AMPK is controversial. Initially, because it is associated with liver kinase B1 (LKB1) and exhibits growth‑suppressive effects, AMPK was considered a tumor suppressor. However, recent studies across various cancer types have clearly demonstrated that AMPK possesses pro‑survival activity, thereby promoting tumor progression, particularly under tumor‑associated stress conditions such as hypoxia, nutrient deprivation, and oxidative stress. This review systematically describes the dual role of AMPK in cancer metabolic reprogramming, summarizes the research progress of AMPK‑targeted cancer therapeutic strategies, and discusses the current challenges and future directions, aiming to provide a theoretical reference for optimizing AMPK‑targeted cancer metabolic therapy.
    Keywords:  AMPK; Metabolic reprogramming; Tumor; Warburg effect
    DOI:  https://doi.org/10.1007/s11033-026-12577-1
  61. Insects. 2026 Jul 25. pii: 765. [Epub ahead of print]17(8):
    Roles of SfHSP70-7 in Thermal Tolerance, Insecticide Adaptability, and Reproductive Performance Under Combined Environmental Stress of the Rice Pest Sogatella furcifera (Hemiptera: Delphacidae).
    Zhenzhen Wang, Yi Yan, Chongfen Yi, Hongwei Zhang, Dengquan Liu, Zhanlie Yang.
      Heat shock protein 70 (HSP70) regulates the stress tolerance and reproductive ability of insects. In this study, the SfHSP70-7 gene was cloned and identified from the rice pest Sogatella furcifera. SfHSP70-7 encodes a typical cytoplasmic HSP70 protein that has a conserved functional domain and is highly similar to the HSP70 homologous protein of Laodelphax striatellus. SfHSP70-7 was found to be widely expressed across all developmental stages, with the highest levels in nymphs and female adults. In terms of tissue distribution, it was particularly abundant in the gut and ovaries. Its expression was strongly induced by high/low temperatures and three insecticides (triflumezopyrim, sulfoxaflor, and imidacloprid), with the maximum induction under heat and triflumezopyrim stress. RNA interference (RNAi) efficiently silenced SfHSP70-7 and significantly increased the susceptibility of S. furcifera to triflumezopyrim and sulfoxaflor, but it had no effect on susceptibility to imidacloprid. RNAi knockdown of SfHSP70-7 markedly reduced survival by 45.5% (30 °C) and 38.9% (35 °C) under heat stress. In addition, gene knockdown can damage the reproductive performance of females by reducing oviposition and egg hatchability. These results indicate that SfHSP70-7 is involved in regulating the heat tolerance, insecticide adaptability, and reproductive regulation mechanism of S. furcifera, providing a potential target for pest control.
    Keywords:  RNA interference (RNAi); Sogatella furcifera; fecundity; thermal tolerance
    DOI:  https://doi.org/10.3390/insects17080765
  62. Hortic Res. 2026 Sep;13(9): uhag146
    MsMTA regulates growth and metabolism in alfalfa (Medicago sativa) through m6A-mediated stabilization of metabolic transcripts.
    Wenwu Qian, Mengzhuo Lin, Huayue Liu, Tingting Wang, JiaMin Cao, Gang Xu, Yunwei Zhang.
      N6-methyladenosine (m6A) is a widespread RNA modification in eukaryotes, yet its contribution to growth and metabolic regulation in perennial leguminous forage crops remains poorly understood. Here, we identify MsMTA, a nuclear-localized m6A methyltransferase in alfalfa (Medicago sativa), as a key regulator of the global m6A landscape, plant architecture, and forage nutritional composition. Suppression of MsMTA expression reduced overall m6A levels and caused a pronounced dwarf phenotype. At the metabolic level, MsMTA knockdown lines showed a strong increase in soluble sugar content, accompanied by only a modest reduction in crude protein and decreased fiber, reflecting a reprogramming of carbon-nitrogen allocation that enhances agronomic quality in alfalfa. Integrated m6A sequencing and transcriptome profiling showed that m6A sites are preferentially enriched in the 3'UTR and that the expression of 549 genes is significantly altered; these genes are mainly involved in oxidation-reduction processes, small-molecule metabolic processes, and organonitrogen compound biosynthesis. Representative metabolic genes, such as GS2 and SDR1, exhibited reduced m6A modification and decreased mRNA stability, directly linking MsMTA-dependent methylation to transcript turnover. Together, these findings establish MsMTA as a central node connecting the m6A epitranscriptome with carbon-nitrogen metabolic homeostasis in alfalfa, and indicate that targeted manipulation of MsMTA-dependent m6A methylation offers a potential route to develop alfalfa cultivars that maintain high protein content while substantially elevating soluble sugars, thereby improving forage yield and quality in leguminous crops.
    DOI:  https://doi.org/10.1093/hr/uhag146
  63. Int J Mol Sci. 2026 Aug 18. pii: 7363. [Epub ahead of print]27(16):
    The Hidden Layer of MicroRNA Regulation in Gynecologic Cancers: IsomiRs, Arm Switching, and RNA Epitranscriptomic Modifications.
    Yussel Pérez-Navarro, César López-Camarillo, Laura C Flores-García, María Elizbeth Alvarez-Sánchez, Alfredo Campoy Ramírez, Yarely M Salinas-Vera.
      MicroRNAs (miRNAs) are key regulators of gene expression that act primarily by binding to target messenger RNAs (mRNAs). However, the biology of miRNAs is more complex than initially thought, with functional complexity extending beyond canonical sequences. A multilayered miRNA regulatory landscape involving isomiR generation, altered 5p/3p strand usage, arm switching, A-to-I RNA editing, and epitranscriptomic RNA modifications operates in eukaryotic cells to regulate miRNA function. Collectively, these mechanisms expand the functional diversity of miRNAs by regulating their biogenesis, stability, strand selection, and target specificity, increasing their functional plasticity and contributing to regulatory heterogeneity found in cells. IsomiRs arise from alternative Drosha/Dicer processing, terminal nucleotide additions, RNA editing, and genetic variation, producing functionally distinct isoforms. Arm switching alters gene regulatory outputs through context-dependent changes in predominant 5p/3p strand usage. In addition, epitranscriptomic RNA modifications, such as m6A and m5C, together with A-to-I RNA editing, represent an additional layer of miRNA regulation. These mechanisms can act directly on miRNAs or their precursors, or indirectly by modifying circRNAs and lncRNAs, thereby altering miRNA availability and function. Together, these processes form a dynamic regulatory network that influences key cancer hallmarks, including cell proliferation, apoptosis, epithelial-mesenchymal transition, metastasis, immune evasion, and therapy resistance. However, the contribution of these non-canonical regulatory layers to tumor-specific miRNA function remains poorly understood. In this review, we explore how isomiR generation, miRNA strand selection, arm switching, and epitranscriptomic regulation expand the functional diversity of miRNAs in gynecologic cancers.
    Keywords:  arm switching; epitranscriptomics; gynecologic cancers; isomiRs; miRNAs
    DOI:  https://doi.org/10.3390/ijms27167363
  64. Front Plant Sci. 2026 ;17 1857506
    Small peptides play a key role as messengers in plant growth, development and abiotic stress resistance.
    Lingjun Lai, Yanling Zhang, Zengting Chen, Guocheng Ren.
      Against the backdrop of global environmental change, plant growth and development face multiple challenges, and a range of abiotic stresses seriously affect their normal growth. In recent years, plant small peptides (SPs)-widely defined as peptides of fewer than 100 amino acids-have emerged as important signaling molecules at the forefront of stress response strategies, playing a key role in regulating plant growth, development, and stress adaptation. This paper reviews the classification of small peptides and their effects on plant growth and development, with a particular focus on the dynamic changes and regulatory mechanisms of various small peptide families under abiotic stress. Studies have shown that small peptides regulate root development, promote cell division and growth, and control reproductive development by participating in intercellular communication, hormone signaling, and stress response networks. The aim of the review is to summarize recent advances in the understanding of SPs in plant growth and development as well as in responses to abiotic stress. We also discuss future research directions concerning the application of these molecules in crop improvement and the enhancement of environmental resilience, thereby providing a theoretical foundation for the elucidation of stress tolerance mechanisms and the breeding of stress-resistant crop varieties.
    Keywords:  abiotic stress; plant growth and development; regulatory mechanisms; signal molecules; small peptides
    DOI:  https://doi.org/10.3389/fpls.2026.1857506
  65. Plant Cell Rep. 2026 Aug 26. pii: 267. [Epub ahead of print]45(9):
    CERES forms a complex with RH37 and eIF4E.
    Isabel C Okeke, Alfonso Muñoz, M Mar Castellano.
       KEY MESSAGE: The translation initiator CERES interacts with the RNA helicase RH37 and bridges the interaction of RH37 with eIF4E.
    Keywords:  CERES; DDX3; DEAD-box helicases; Ded1; EIF4E1; Protein synthesis; Translation initiation
    DOI:  https://doi.org/10.1007/s00299-026-03888-5
  66. ACS Chem Biol. 2026 Aug 21. 21(8): 2012-2020
    Identification of the Site of the Fe-S Cluster in CPSF30 via Metal-Coupled Oxidation-Mass Spectrometry.
    Matthew S Hursey, Jordan D Pritts, Danté T Johnson, Melanie M Chestnut, Abigail D Reitz, Jasper G Ballot, David P Goldberg, Lisa M Jones, Veronika A Szalai, Sarah L J Michel.
      Cleavage and polyadenylation specificity factor 30 (CPSF30) is a zinc finger protein that plays a key role in pre-mRNA processing by recognizing specific AU-rich sequence elements to facilitate polyadenylation. CPSF30 contains five highly conserved domains made up of three cysteines and a single histidine residue (CCCH, where C = cysteine; H = histidine). These domains coordinate both Zn and an essential 2Fe-2S cluster required for high-affinity RNA binding. The location of the 2Fe-2S cluster within the five CCCH domains and its function have proven elusive. Here, we apply metal-catalyzed oxidation mass spectrometry (MCO-MS) to identify the 2Fe-2S cluster site within CPSF30. By first determining its redox properties and then initiating Fenton chemistry, we localized the Fe-S cluster to the second CCCH domain. The effect of redox state on RNA binding was then assessed, and it was determined that the Fe-S site is a structural domain. The effect of redox status in THP-1 cells on CPSF30 was then investigated, and the redox properties of the cluster were linked to protein abundance under hypoxic and normoxic stress. Together, this work describes a new approach to identify Fe-S sites in complex metalloproteins that house multiple metal cofactors, suggests a mechanism for metal-mediated RNA recognition by CPSF30, and reveals redox-mediated control of CPSF30 in cells.
    DOI:  https://doi.org/10.1021/acschembio.6c00449
  67. Nucleic Acids Res. 2026 Aug 24. pii: gkag803. [Epub ahead of print]54(16):
    Assembly of exon junction complexes on spliceosomes begins before spliceosome activation.
    Elizabeth T Abshire, Lynne E Maquat.
      Despite the importance of exon junction complexes (EJCs) to co- and post-transcriptional gene control, how and when the EJC core of EIF4A3, RBM8A, and MAGOH, and the peripheral factors of the alternative RNPS1-EJC and CASC3-EJC, assemble on spliceosomes remain unclear. Existing characterizations that order EJC assembly on spliceosomes offer different conclusions. Using immunoprecipitations (IPs) of EIF4A3, RNPS1, or CASC3 in the presence of RNase I followed by liquid chromatography followed by tandem mass spectrometry (LC-MS/MS) analyses of human HEK293T cells, we expand upon those splicing factors that associate with EJC constituents. Referencing these data against existing cryogenic electron microscopy (cryo-EM) spliceosome structures at different stages of pre-messenger RNA (pre-mRNA) splicing, coupled with data from a series of western blots of nuclear fractions before and after IP, we report that EIF4A3, RBM8A, MAGOH, and RNPS1 associate with assembled but inactive spliceosomes. This is followed by CASC3 joining to late activated spliceosomes. Our work bridges long-standing gaps in understanding EJC assembly on spliceosomes.
    DOI:  https://doi.org/10.1093/nar/gkag803
  68. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2534325123
    Loss of epitranscriptomic mitochondrial RNA surveillance drives epithelial type I interferon and inflammation in autoimmunity.
    Alejandro Arco-Hierves, Konstantina Pamboukas, Linda Bilonda Mutala, Lukasz S Borowski, Celine Mayet, Paul Mazet, Sacha E Silva-Saffar, Dory Vergallo, Anna Paszek, Marta M Dilling, Laurie Askenatzis, Juliette Pascaud, Philippe Labrot, Charlene Lasgi, Johannes N Spelbrink, Albertas Navickas, Thibaut Naninck, Nabila Seddiki, Arnaud Tete, Roman J Szczesny, Gaetane Nocturne, Xavier Mariette, Rami Bechara.
      Chronic interferon (IFN) activation is a hallmark of autoimmune diseases such as systemic lupus erythematosus and Sjögren's disease (SjD), where epithelial cells are key contributors. Although viral and retroelement triggers have been proposed as triggers, direct evidence in patient tissues is limited, and endogenous mechanisms of epithelial IFN dysregulation remain unclear. Mitochondrial double-stranded RNA (mt-dsRNA) is a potent type I IFN (IFN-I) inducer, but its regulation in epithelial cells is poorly understood. We identify a mechanism in which the RNA methyltransferase METTL3 stabilizes REXO2 mRNA in primary salivary gland epithelial cells through N6-methyladenosine (m6A) modification. REXO2 encodes a mitochondrial exonuclease that controls mt-dsRNA. METTL3 inhibition reduces REXO2, causing mt-dsRNA accumulation and IFN-I signaling amplification and inflammation. Single-cell and bulk transcriptomic analyses, together with immunofluorescence of salivary gland tissues from SjD patients and controls, reveal reduced REXO2 expression and elevated IFN-I signatures in SjD. Rexo2 is likewise downregulated in epithelial cells of a spontaneous SjD mouse model. REXO2 loss amplifies IFN-I responses and inflammation across several epithelial contexts, while methyl donors restore REXO2 and dampen IFN activation, highlighting a targetable regulatory checkpoint in IFN-driven autoimmune diseases, alongside potential parallel stress pathways.
    Keywords:  RNA methylation; Sjögren’s disease; autoimmunity; interferon; mitochondria
    DOI:  https://doi.org/10.1073/pnas.2534325123
  69. Aging Cell. 2026 Sep;25(9): e70664
    Oxygenaging: A Physiological Framework for Geroscience.
    Stefano Donega, Kenneth W Fishbein, Paolo Dominelli, Allison B Herman, Rafael de Cabo, Myriam Gorospe, Luigi Ferrucci.
      The stepwise movement of oxygen from the atmosphere to the mitochondria, the "oxygen cascade", is one of the most tightly regulated systems in physiology. Despite decades of mechanistic study, it has remained quite unexplored in Geroscience. This oversight should be reconsidered. In young organisms, hypoxic stress (whether environmental or tissue-specific) activates a complex adaptive response to preserve energetic stability via restraining anabolic pathways, optimizing mitochondrial performance, and reinforcing cellular quality control systems. With advancing age, angiostatic signaling increases, endothelial metabolism becomes dysregulated, and overall alveolar ventilation and pulmonary gas exchange (ventilation-perfusion matching and diffusion capacity) become less efficient. These changes promote microvascular rarefaction and low-grade but persistent mismatches between oxygen delivery and demand at the tissue level, ultimately destabilizing cellular function. In this review, we propose that the gradual erosion of oxygen homeostasis is not simply a byproduct of aging, but also a driver of molecular damage and functional decline. We examine the aging oxygen cascade through the framework of resilience biology, focusing on mechanisms such as mitochondrial electron leaks, oxidative stress amplification, iron dyshomeostasis, ferroptosis, and epigenetic remodeling. We also discuss interventions that alter oxygen availability, such as intermittent hypoxia, hyperbaric oxygen therapy, and hypoxic-hyperoxic training. These approaches demonstrate adaptive potential, but they also highlight the narrow margin between beneficial stress and injury. We propose "Oxygenaging" as a unifying framework in which aging associates with the progressive loss of equilibrium across the oxygen cascade, linking systemic oxygen transport to mitochondrial function, genomic stability, and cellular resilience.
    Keywords:  Oxygenaging; RNA splicing; aging; energy; epigenetics; hyperoxia; hypoxia; hypoxia inducible factor 1 (HIF1); mitochondria; oxygen
    DOI:  https://doi.org/10.1111/acel.70664
  70. J Gen Appl Microbiol. 2026 Aug 26.
    Developing an assay system for screening inhibitors of Hfq-mediated RNA metabolism.
    Ayako Takada, Masaaki Wachi.
      Hfq is an RNA chaperone conserved across diverse bacterial lineages that regulates gene expression by facilitating the pairing of small RNAs with their target mRNAs. It influences both the translation and stability of specific transcripts, thereby contributing to complex post-transcriptional regulatory networks. We have previously shown that overproduction of Hfq inhibits cell division by suppressing the expression of the essential cell division protein FtsZ. Based on this observation, we developed a novel antibiotic screening system using an Escherichia coli strain harboring an IPTG-inducible hfq gene to identify compounds that interfere with Hfq-mediated RNA metabolism. We tested representative inhibitors of DNA synthesis, protein synthesis, and cell wall synthesis; however, none restored colony formation. In contrast, rifampicin, an inhibitor of RNA polymerase, restored colony formation, as expected for a compound interfering with Hfq function. Sublethal concentrations of rifampicin restored colony formation of the Hfq-overproducing cells. Western blot analysis revealed that Hfq expression levels decreased upon rifampicin treatment, indicating that rifampicin was a false-positive hit. To eliminate such false-positive hits, a rifampicin-resistant rpoB mutation was introduced into the indicator strain. As expected, rifampicin did not restore growth of the rifampicin-resistant rpoB strain. This assay provides a useful platform for identifying compounds that interfere with Hfq-mediated RNA metabolism.
    Keywords:  Escherichia coli; Hfq; RNA metabolism; antibiotics; screening system
    DOI:  https://doi.org/10.2323/jgam.2026.08.001
  71. Protein Eng Des Sel. 2026 Aug 27. pii: gzag024. [Epub ahead of print]
    SARS-CoV-2 Orf3a Protein Interaction Mapping Using Unnatural Amino Acid Incorporation.
    Eryn Lundrigan, Noreen Ahmed, John Paul Pezacki.
      Mapping transient protein-protein interactions remain a major challenge in studying viral host-pathogen interfaces. While some virus-host interactions are stable and readily captured, the majority are highly dynamic, reflecting the need for a small number of viral proteins to engage distinct host factors at different stages of the life cycle. Here, we employ a protein engineering strategy based on the site-specific incorporation of the non-canonical amino acid p-azido-L-phenylalanine (AzF) to enable photo-crosslinking proteomic analysis of the SARS-CoV-2 accessory protein Orf3a in live cells. Genetic installation of AzF at residue K198 of Orf3a permitted UV-induced covalent capture of proximal host interacting proteins, overcoming challenges associated with membrane localization and limited protein abundance. A total of 248 high-confidence Orf3a-interacting proteins were reproducibly identified and subjected to gene ontology analysis, revealing enrichment in innate immune signaling, antiviral defense, RNA processing, and viral replication-associated pathways. Orf3a is an accessory protein that functions as a viroporin and traffics across multiple cellular compartments, and was found to interact with host RNA helicases, RNA-binding proteins, immune regulators, and metabolic enzymes implicated in SARS-CoV-2 infection. Together, these results demonstrate that genetically encoded, site-specific photo-crosslinking enables selective capture of transient interactions that are often missed by nonspecific 254nm UV crosslinking approaches and highlights Orf3a as a multifunctional protein that engages diverse host pathways. More broadly, this study establishes a generalizable framework for leveraging non-canonical amino acid-based protein engineering approaches to interrogate dynamic host-pathogen interactions.
    Keywords:  AzF; Orf3a; Protein Interaction Mapping; SARS-CoV-2; Unnatural Amino Acid; Viral Protein
    DOI:  https://doi.org/10.1093/protein/gzag024
  72. Int J Mol Sci. 2026 Aug 10. pii: 7156. [Epub ahead of print]27(16):
    Convergent Mechanistic Pathways Driving the Anaplastic Phenotype in Thyroid Cancer.
    Anthony Centone, Nicole R DeSouza, Nan Yang, Shaun Desai, Augustine Moscatello, David Garber, Steven Hemmerdinger, Janine M Rotsides, Mike Yao, Raj K Tiwari, Jan Geliebter, Xiu-Min Li.
      Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive follicular cell-derived malignancy characterized by rapid progression, profound dedifferentiation, and marked resistance to conventional therapy. Despite frequent involvement of major oncogenic pathways, ATC does not exhibit a universal driver mutation, suggesting that its pathogenesis reflects convergence upon shared biological hallmarks rather than dependence on a single molecular event. This review describes the principal mechanistic programs that define the ATC phenotype: disruption of cell-cycle and apoptotic control through alterations in TP53, CDKN2A/B, and aberrant MAPK activation; metabolic adaptations involving glycolysis, glutaminolysis, and mitochondrial one-carbon metabolism; reprogramming of canonical stress response pathways including ER stress and hypoxia signaling; and dynamic remodeling of the tumor microenvironment through cytokine-driven paracrine networks and immune modulation. Collectively, these processes cooperate to generate a highly proliferative, stress-tolerant, immune-inflamed yet immunosuppressed tumor state. A mechanistic understanding of these convergent pathways is essential for rational therapeutic development and for overcoming the profound clinical resistance that defines ATC.
    Keywords:  ER stress; anaplastic thyroid cancer; hypoxia signaling; metabolic reprogramming; tumor microenvironment
    DOI:  https://doi.org/10.3390/ijms27167156
  73. Biotechnol Lett. 2026 Aug 27. pii: 107. [Epub ahead of print]48(5):
    5' untranslated region (5' UTR) of bovine β-globin in the mRNA constructs translates different types of antigenic proteins.
    Basavaraj Sajjanar, Shreya Gopinath, Prasanth Nadarajan, Vishnu Kiran Marreddy, Narayanan Krishnaswamy, Viswas K Nagaleekar, Madhusudan Hosamani, B P Sreenivasa, Pallab Chaudhuri, Suresh H Basagoudanavar.
      Synthetic messenger RNA (mRNA) is emerging as next generation vaccine platform. As natural 5'UTRs of particular genes do not work for other than its own mRNA, it is essential to identify an ideal 5'UTR supporting higher translation efficiency for different antigens. Six natural 5'UTRs derived from α, β-globin genes of host animals and other viral genes were cloned upstream to the coding sequences of reporter proteins. The corresponding capped mRNA were produced through in vitro transcription and the translation efficiency was assessed using flow cytometry, bioluminescence, immunofluorescence and western blot experiments. The results revealed higher translation of reporter proteins by bovine β-globin 5'UTR in different cell lines. Further, the chosen 5'UTR supported mRNA translation to produce different antigenic proteins such as rabies virus glycoprotein (RVG), major structural protein of foot and mouth disease virus (VP1) and bacterial epsilon toxoid protein (Eptx). Bovine -globin 5'UTR not only increased the translation efficiency of reporter proteins but also supported the expression of different antigenic proteins. Hence, bovine -globin 5'UTR can be used in the mRNA vaccine designs against animal diseases.
    Keywords:  5’ untranslated region (5’ UTR); Antigenic proteins; Reporter genes; Translation efficiency; mRNA vaccine
    DOI:  https://doi.org/10.1007/s10529-026-03778-6
  74. Proc Natl Acad Sci U S A. 2026 Sep;123(35): e2618832123
    RNA aptamers for sodium and lithium are abundant in mammals.
    Neil White, Gabriel Belem de Andrade, Aya Narunsky, Christopher King, Narasimhan Sudarsan, Ronald R Breaker.
      Riboswitches are common in the bacterial domain of life where they regulate gene expression in response to binding metabolites, elemental ions, or other small ligands. We used comparative sequence analyses to identify numerous RNA motifs in humans and other mammals that are similar in sequence and structure to bacterial riboswitch aptamers for cationic sodium and lithium. Candidates are found in the mRNA transcripts for ~70 genes relevant to ion conductance, neuronal development and function, or to various neurological diseases. Bioinformatic and biochemical analyses support the hypothesis that mammals make extensive use of these RNA aptamers to selectively bind Na+ and Li+. These structured RNA domains are often located in regions of mRNAs or their putative antisense transcripts that suggest they are components of riboswitches. Such associations also expose links between these alkali metal ions and genes whose expression is likely under monovalent ion regulation. These findings are also consistent with the hypothesis that Li+ is a natural contributor to the regulation of genes relevant to certain mental disorders.
    Keywords:  GNPAT; SCN5A; alkali metal; bipolar disorder; riboswitch
    DOI:  https://doi.org/10.1073/pnas.2618832123
  75. Int J Biol Macromol. 2026 Aug 25. pii: S0141-8130(26)04127-9. [Epub ahead of print] 154181
    Deletion of the MALAT1 RNA 3' end promotes transcript decay and inhibits proliferation in gastric and breast cancer cells.
    Aramis Cortes-Arias, Valeria Valdes, Marcelo Muñoz-González, Diego Leiva, Andrew Acevedo, Michelle Tobar-Lara, Nicole Farfán, Lilly Oni, Eduardo Quiñones-Medina, Veronica A Burzio, Adriana Rojas, Roberto Munita, Srinivas Somarowthu, Fernando J Bustos, Rodrigo Aguilar.
      The long non-coding RNA MALAT1 is a conserved oncogenic driver whose function relies on a 3' triple-helix motif. While its biochemistry is well-characterized in vitro, the endogenous requirement for this motif in regulating the stability of the transcript and other genes residing in its locus remains unclear. In this study, we employed a dual-sgRNA CRISPR-Cas9 approach to systematically excise triple-helix-forming sequences from the native MALAT1 locus in gastric (AGS) and breast (MCF7) cancer cells. Our findings demonstrate that the 3' end strongly contributes to MALAT1 stability. Perturbations ranging from genomic deletions to a single-base changes trigger transcript collapse and rapid exonucleolytic decay, while the biogenesis of the small RNA mascRNA (a byproduct of MALAT1, also involved in cancer) remains decoupled and unaffected. In cellulo, DMS probing reveals that edited transcripts retain structural complexity in the 3' region. Phenotypically, structural disruption of the 3' end significantly impairs proliferation of both cancer cellular models. These results identify the 3' triple-helix as a determinant of MALAT1 stability and provide endogenous validation for its role in the analyzed AGS and MCF7 cells.
    Keywords:  Cancer; Long non-coding RNAs; MALAT1; lncRNA
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.154181
  76. Front Aging Neurosci. 2026 ;18 1910154
    Proteostasis breakdown and aggregate diversity in aging and neurodegenerative disease.
    Zohaib Nisar Khan.
      Protein aggregation and proteostasis decline are central features of aging and neurodegenerative disease, arising from progressive impairment of protein quality-control systems and transitions into aggregation-prone states. During aging, diverse proteins, including metabolic and proteostasis-related factors, gradually accumulate in aggregated forms as proteostasis capacity declines. Although these aggregates often remain compatible with cellular function, increasing aggregate burden progressively challenges proteostasis resilience. Neurodegenerative diseases are characterized by the emergence and amplification of highly toxic, structurally ordered protein assemblies, including amyloid-β (Aβ) and tau, which exist along a continuum with broader age-associated proteome instability rather than as entirely distinct phenomena. Oxidative and metabolic imbalances promote non-enzymatic post-translational modifications (PTMs), including cysteine oxidation, S-nitrosylation, and carbonylation, which alter protein structure, impair degradation pathways, and facilitate misfolding and aggregation. Here, we compare oxidative PTM-driven aggregates observed during aging with disease-associated protein assemblies, highlighting both shared biophysical mechanisms and distinct pathological outcomes. We propose a threshold model in which the cumulative burden of oxidative PTMs, protein misfolding, and impaired clearance progressively erodes proteostasis capacity, increasing susceptibility to the emergence of selective, self-amplifying aggregates. By integrating intracellular quality-control systems with extracellular clearance pathways, including glymphatic and meningeal lymphatic networks, this framework provides a mechanistic perspective on how aggregate diversity evolves toward disease-associated pathology and suggests therapeutic strategies that combine aggregate-specific targeting with restoration of global proteostasis and clearance capacity.
    Keywords:  aging; amyloid-β and tau; glymphatic system; neurodegenerative disease; protein aggregation; proteostasis
    DOI:  https://doi.org/10.3389/fnagi.2026.1910154
  77. Molecules. 2026 Aug 20. pii: 2901. [Epub ahead of print]31(16):
    Beyond the Capsid: How Can Post-Translational Modifications Modulate the Multifunctionality of the Orthoflavivirus Capsid Protein?
    Nathane C Mebus-Antunes, Dayane Henriques, Andrea T Da Poian.
      The orthoflavivirus capsid (C) protein is a multifunctional protein that plays essential roles throughout the viral life cycle. Besides viral RNA encapsidation for nucleocapsid assembly, it associates with lipid droplets, interacts with host proteins, and translocates to the nucleus, although its nuclear functions are still poorly understood. How these diverse activities are coordinated remains an open question. Post-translational modifications (PTMs), which are key regulators of protein function, have emerged as critical modulators of the infection cycle in many RNA viruses. However, little is known about the occurrence and functional significance of PTMs in orthoflavivirus C proteins. Here, we review the current evidence on PTMs in orthoflavivirus C proteins and integrate insights from studies of other RNA viruses to propose mechanisms by which PTMs may regulate C protein function. To complement this review, we performed a comparative in silico analysis of predicted PTM sites in the C proteins of dengue, Zika, West Nile, and Japanese encephalitis viruses. By integrating PTM predictions with experimentally validated modification sites, residue conservation, and structural mapping, we identified conserved regulatory hotspots that represent promising targets for future experimental validation. Together, these findings highlight PTMs as an underexplored regulatory mechanism in orthoflavivirus capsid biology and provide a framework for future mechanistic investigations.
    Keywords:  RNA virus; capsid protein; orthoflavivirus; post-translational modifications
    DOI:  https://doi.org/10.3390/molecules31162901
  78. Mol Neurobiol. 2026 Aug 25. pii: 854. [Epub ahead of print]63(1):
    Beyond the Ribosome: The Expanding Role of the Nucleolus in Neurodegenerative Pathways.
    Diego Iacono, Gloria C Feltis.
      The nucleolus, long defined by its canonical role in ribosome biogenesis, has emerged as a critical nexus for cellular homeostasis, stress sensing, and disease pathogenesis. This article synthesizes a broad range of evidence to construct a comprehensive model of the nucleolus in the context of aging and neurodegeneration. We begin by detailing its fundamental architecture and the intricate process of ribosome production, before exploring the paradigm-shifting discovery of its vast, non-canonical proteome, which implicates it in DNA repair, cell cycle control, and genome stability. A central theme is the nucleolus's function as a primary cellular stress sensor, which, upon disruption by genetic, metabolic, or proteotoxic insults, initiates the nucleolar stress response. We provide a detailed examination of the downstream signaling cascades, focusing on the canonical p53-MDM2 axis and the interconnected mTOR pathway, which together translate nucleolar status into decisions of cell fate, including apoptosis and cell cycle arrest. We then focus on the brain, presenting the neuropathological and morphological alterations of the nucleolus-such as atrophy, fragmentation, and changes in volume-that serve as hallmarks of normal aging and neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease, and C9orf72-linked ALS/FTD. We explore the deep regulatory layers of epigenetics, where DNA methylation and histone modifications of ribosomal DNA genes are dysregulated in disease, and discuss how multi-omics approaches are unraveling the complex molecular landscape of nucleolar function. Finally, we introduce the emerging concept of a gut-brain-nucleolus axis, proposing how systemic factors like the gut microbiome may influence neuronal health by triggering nucleolar stress through inflammatory and metabolic mediators. Overall, by highlighting the nucleolus as a convergence point for diverse pathogenic pathways, we frame it as a promising and druggable target for novel therapeutic strategies aimed at promoting neuronal resilience and combating neurodegenerative diseases.
    Keywords:  Aging; Alzheimer’s disease; Amyotrophic lateral sclerosis; Epigenetics; Gut–brain–nucleolus axis; Neurodegeneration; Nucleolar stress; Nucleolus; Parkinson’s disease; p53
    DOI:  https://doi.org/10.1007/s12035-026-06146-7
  79. Curr Opin Pharmacol. 2026 Aug 27. pii: S1471-4892(26)00058-5. [Epub ahead of print]90 102662
    Mitochondria as a therapeutic platform in inflammatory and degenerative disorders: mechanisms, biomarkers, and translational challenges.
    Lamiaa M ElAbbasy.
      Mitochondrial dysfunction has emerged as a convergent pathogenic mechanism across inflammatory and degenerative disorders, functioning not as a passive consequence but as an active amplifier of tissue injury, immune dysregulation, and impaired repair. Consistently observed mitochondrial abnormalities include excessive reactive oxygen species production, impaired oxidative phosphorylation, defective mitophagy, altered fission-fusion dynamics, and release of mitochondrial danger-associated molecular patterns, particularly cell-free mitochondrial DNA (cf-mtDNA), which serves both as a proinflammatory mediator and a potential circulating biomarker of disease activity. These alterations create self-reinforcing networks in which mitochondrial stress promotes innate immune activation, sustains inflammatory signaling, and accelerates structural or functional decline in vulnerable tissues. Mitochondria-targeted pharmacology has expanded rapidly, encompassing organelle-directed antioxidants, modulators of mitochondrial quality control, biogenesis or metabolic enhancers, nano-enabled delivery platforms, and emerging mitochondrial replacement strategies. Despite strong mechanistic appeal and encouraging preclinical data, clinical translation remains limited by the absence of validated pharmacodynamic biomarkers, an incomplete understanding of disease endotypes, inconsistent tissue target engagement, delivery barriers to mitochondria-rich compartments, and poor predictive value of animal models for human disease biology. The cf-mtDNA and related mitochondrial signatures are increasingly attracting attention for patient stratification, phenotyping, and therapeutic monitoring, although assay standardization remains unresolved. This review focuses on the core mechanisms that link mitochondrial dysfunction to disease progression. It also examines biomarker development and the major barriers to translation. Emerging approaches such as nanotechnology and mitochondrial replacement are discussed as supplementary strategies, not as the main focus of the review.
    DOI:  https://doi.org/10.1016/j.coph.2026.102662
  80. Genes (Basel). 2026 07 31. pii: 911. [Epub ahead of print]17(8):
    RNA Splicing Dysregulation in Parkinson's Disease.
    Maria Giusy Bruno, Giacomo Menichetti, Angela Valentino, Aqsa Javaid, Francesca Belpinati, Alessandra Ruggiero, Maria Teresa Valenti, Giovanna Paolone, Fabio Cavaliere, Elisabetta Trabetti, Maria Grazia Romanelli, Cristina Bombieri.
      Genetic mutations, altered RNA regulation, and protein aggregation are the main hallmarks of Parkinson's disease (PD), a neurodegenerative disorder. Investigation into the molecular basis of the disease revealed that post-transcriptional regulation, specifically RNA processing, contributes to neuronal vulnerability in PD. Alterations in alternative splicing affecting genes involved in neuronal function and cellular homeostasis have been reported in PD, including SNCA, LRRK2, MAPT, PRKN, and BIN1. These alterations impact central neuronal pathways, including cytoskeletal maintenance, mitochondrial function, synaptic activity, oxidative stress, and intracellular trafficking. This review aims to provide an overview of alternative splicing in key PD gene transcripts, with a focus on their roles in pathogenesis and disease progression. Emerging data suggest that dysregulation of RNA binding proteins (RBPs) may influence RNA processing in PD. We will examine current evidence on the RNA regulatory networks in PD, highlighting the role of transcript isoforms and RBPs in neuronal dysfunction. Finally, we will discuss emerging experimental models such as 3D-brain organoids that offer new opportunities to investigate splicing regulation.
    Keywords:  Parkinson’s disease; RBPs; RNA processing; brain organoids; splicing
    DOI:  https://doi.org/10.3390/genes17080911
  81. Environ Health (Wash). 2026 Aug 21. 4(8): 1741-1753
    Cotinine Promotes Cancer Cell Proliferation and m1A RNA Methylation in Smoking-Associated Lung Cancer by Targeting PLK1/β-Catenin/TRMT6 Axis.
    Panlong Li, Xuyun Peng, Sihuang Wu, Jiani Wang, Yiju Huang, Zexiao Lin, Yang Yang, Weicheng Liang.
      Nicotine is the most abundant alkaloid in tobacco, and 70%-80% of its metabolites are cotinine. In terms of that, numerous cigarettes are consumed worldwide, resulting in a large amount of cotinine being released into the environment and posing potential hazards. However, the biological effects of cotinine are poorly understood. In the current study, we identified that the oncogene Polo-like kinase 1 (PLK1) is a direct target of cotinine, and cotinine could upregulate the protein level of PLK1. Public epidemiological data indicated a positive correlation between PLK1 expression and smoking. Subsequent studies validated that PLK1 directly interacted with β-catenin, leading to transcriptional activation of tRNA methyltransferase 6 (TRMT6), a canonical methyltransferase involved in m1A methylation modification of RNA. Dot blot showed that cotinine enhanced m1A RNA methylation in lung cancer cells. Public epidemiological data also demonstrated a positive correlation between the expression of TRMT6 and smoking. Knockdown of TRMT6 impaired cell proliferation and sensitized lung cancer cells to common chemotherapeutic agents. Taken together, our current study indicated a previously unknown role of cotinine in promoting cancer cell proliferation by targeting the PLK1/β-catenin/TRMT6 axis, which may shed light on the connection between smoking and RNA modifications.
    Keywords:  RNA methylation; cotinine; epigenetics; lung cancer; smoke
    DOI:  https://doi.org/10.1021/envhealth.6c00013
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