bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–09–20
73 papers selected by
Cédric Chaveroux, CNRS
  1. Neuronal translational control in physiology, infection, and inflammation.
  2. Rewriting the brain: m6A RNA methylation as an emerging epitranscriptomic regulator in major depressive disorder.
  3. Viral control of translation: rise of the ribosome.
  4. From Cellular Stress to Systemic Adaptation: The Circadian Clock and Stress Response at Cellular and Systemic Levels.
  5. Medulloblastoma-associated mutations in the RNA helicase DDX3X/DED1 cause defects in the translational response to TORC1 inhibition.
  6. Ivermectin Inhibits Stress Granule Clearance by Blocking the De Novo Synthesis of Hsp70 in Neuroblastoma Cells.
  7. Selective remodeling of snoRNA and sdRNA biology in glioblastoma.
  8. The Paradox of Tau and RNA-Binding Proteins: How Adaptive Stress Granule Regulation Becomes Pathological with Aging.
  9. Mitokines as bioenergetic stress signals in cardiovascular disease: mitochondrial communication, endocrine adaptation, and translational implications.
  10. N6-methyladenosine as a potential epitranscriptomic immune rheostat during SARS-CoV-2 infection.
  11. Transcript-wide m6A methylation defines the efficiency of cap-independent translation initiation.
  12. The hnRNPA1 D262V amyotrophic lateral sclerosis (ALS) mutation is linked to mitochondrial dysfunction.
  13. Post-transcriptional regulation of erythropoiesis.
  14. tRNA‑derived RNAs in hepatic diseases: From biological functions to clinical translation (Review).
  15. Programmed ribosomal frameshifting triggers translational stress to promote viral replication.
  16. Anagrelide remodels the PDE3A-SLFN12 interactome to associate with translation initiation machinery in cancer cell lines.
  17. m6A-Targeted Cancer Therapy: Molecular Targets, Inhibitors, and Nanodelivery Strategies.
  18. Cellular stress leading to epithelial cell dysfunction in Sjögren's syndrome.
  19. Ribosomal RNA transcription in normal and leukemic hematopoiesis.
  20. Advances of N6-methyladenosine RNA methylation in tree species.
  21. m(6)A RNA Methylation in aging and age-related diseases.
  22. Cryo-EM Structure of the 50S Ribosomal Subunit from the Phytopathogen Xanthomonas citri pv. glycines.
  23. METTL14-Mediated lncRNA MSTRG.292666.16 m6A Modification Promotes the Progression of Non-Small-Cell Lung Cancer Through the MAPK Pathway.
  24. The RNA structural code: orchestrating gene expression and enabling precision therapies.
  25. MiR-662 impairs C/D box snoRNA expression and rRNA 2'-O-ribose methylation marks.
  26. Genetics of α-Synuclein: The Prime Pathological Player of Parkinson's Disease.
  27. Nitric oxide signaling and mitophagy in Parkinson's disease: implications for aerobic exercise-related neuroprotection.
  28. Regulation of TIPIN and replication fork dynamics by USP37.
  29. L-Cysteine and N-Acetylcysteine Supplementation Improves Clinical Outcome in a Patient With COXPD10.
  30. N4BP1 uses tandem KH domains to associate with EDC4 and mRNA decapping factors in P-bodies.
  31. Target, silence, replace: a review on RNA-based drugs in modern medicine.
  32. Regulation and function of the HPV16 CircE7 RNA.
  33. Human m6A demethylase FTO modulates the flowering time of tomato plants under low-temperature stress.
  34. Polyamine metabolic enzyme SAT1 remodels the neuronal transcriptome and rescues α-synuclein toxicity in Drosophila.
  35. RNA m6A modification-regulated ferroptosis in cancer: mechanism and therapeutic potential.
  36. Mitochondria‑associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review).
  37. RBM15 Contributes to Bladder Carcinoma Progression via m6A-dependent Stabilization of IFI6 mRNA.
  38. Transcriptomic analysis reveals physiological adaptations and immune system modulation in Romanian Holstein cattle during heat stress exposure.
  39. Zinc-dependent turnover of ZIP3 transporter mRNA by trypanosome ZNK1.
  40. Deletion Analysis of Phase Separation, Amyloid Formation and Prion Propagation by the Intrinsically Disordered Region of Yeast Sup35 Protein.
  41. Heat Shock Proteins in Cancer: Mechanisms and Therapeutic Targeting.
  42. From RNA design to delivery: Computational strategies for functional RNA therapeutics.
  43. Experimental and Computational Approaches to Identify RNA-Protein Interactions.
  44. An OsSK12/13-OsERF60-OsHsfA2c module regulates heat stress tolerance in rice.
  45. Protein Arginine Methylation of the Translation Initiation Factor eIF1A Increases Usage of a Near-cognate Start Codon.
  46. Chemo-selective proteomics in microbial systems.
  47. circNfix attenuates acute kidney injury by driving m6A-dependent degradation of YTHDF2 to stabilize DAPK2 mRNA.
  48. The Effects of Disrupting Ca2+ Homeostasis on the ERs and Lipid Metabolism in the Hepatopancreas of Penaeus vannamei Exposed to Ammonia Stress.
  49. Function within disorder: Small heat shock proteins use different functional regions to chaperone tau aggregation.
  50. Transcription elongation mechanisms that control gene expression in erythropoiesis.
  51. Analysis of proteasome stress in different cell types defines a conserved transcriptional response signature and its modulation with aging.
  52. EvoMut: A computational framework for engineering oxidative stability in proteins.
  53. LRRK2: Molecular Mechanisms in Parkinson's Disease.
  54. [Expression of Concern] RIP kinase‑mediated ROS production triggers XAF1 expression through activation of TAp73 in casticin‑treated bladder cancer cells.
  55. Elucidating the Requirements for microRNA-Mediated Upregulation Enables Reengineering of Upregulatory Sites.
  56. Advances in Poultry RNA-Omics Research: Technologies, RNA Information Layers, and Applications in Complex Traits.
  57. RNA demethylase FTO uses conserved aromatic residues to recognize the mRNA 5' cap and promote efficient m6Am demethylation.
  58. Molecular basis of tRNA substrate recognition and modification by the atypical SPOUT methyltransferase Trm10.
  59. Short-lived lncRNAs as candidate kinetic sensors of cellular stress.
  60. Organelle-centered ISG15 biology: distinguishing covalent ISGylation from interferon-associated responses.
  61. Damage-Associated Molecular Patterns in Mesothelioma: Drivers of Inflammation and Therapeutic Targets.
  62. RNF5: an emerging therapeutic target for modulating immunity and metabolism.
  63. Dual regulation of the receptor-like kinase BIR1 involves site-directed transcript cleavage and 5'-leader-mediated translational control.
  64. Nicotine modulates α7nAChR associated ceramide-mitochondrial stress responses in Parkinsonian models.
  65. Heat shock proteins as modulators of cardiovascular health and disease: From cellular stress to clinical targets.
  66. Differential Modulation of the DR5-JNK-PD-L1 Signaling Axis by TRiC/CCT Subunits CCT7 and CCT2 Shapes Tumor Immune Evasion in Lung Adenocarcinoma.
  67. The RNA-Binding Protein ELAVL4/HuD Promotes Stress-Associated Tumor Survival in Neuroendocrine Cancers.
  68. Ashwin and FAM98 paralogs define nuclear and cytoplasmic RNA ligase complexes for tRNA biogenesis.
  69. Mitochondrial Remodeling, Cytoskeletal Dynamics, and Translational Control During Drosophila Spermatid Elongation: An Integrative Review.
  70. PCBP2 facilitates miR-93-5p-mediated repression of GDF11 in HCC cell lines.
  71. Decoding oxidative stress-driven metabolic reprogramming in skeletal degenerative diseases: natural phytochemicals as precision metabolic modulators.
  72. Bacterial stress responses lower mRNA-protein level correlations.
  73. Lactate-driven lactylation reprograms chondrocyte fate and joint inflammation in osteoarthritis: linking metabolism with epigenetic regulation.
  1. Cell Chem Biol. 2026 Sep 14. pii: S2451-9456(26)00321-1. [Epub ahead of print]
    Neuronal translational control in physiology, infection, and inflammation.
    Felix Fischbach, Henrike K Grosshans, Lars Binkle-Ladisch, Manuel A Friese.
      Neurons are highly specialized cells whose function depends on dynamic regulation of gene expression. With increasing subcellular compartmentalization, neuronal gene expression becomes less dependent on transcription in the perinuclear region and tends to be increasingly controlled by local translation. The integrated stress response is a central, evolutionarily conserved pathway of translational regulation that maintains neuronal homeostasis through precise control of protein synthesis. Transient cellular stress, such as neuronal infection, adaptively activates this pathway, whereas persistent dysregulation, as observed in neuroinflammation and neurodegeneration, promotes neuronal dysfunction and damage. Here, we summarize key neuron-specific mechanisms governing translational homeostasis and discuss adaptive and detrimental molecular processes associated with neurological disease. Understanding this tightly regulated pathway and its context-dependent effects provides a framework for identifying mechanisms of neuronal vulnerability and for developing therapeutic strategies that target translational control in neurological disorders, while preserving its essential adaptive functions under physiological and acute stress conditions.
    Keywords:  CNS infection; integrated stress response; neurodegeneration; neuroinflammation; proteostasis; translational control
    DOI:  https://doi.org/10.1016/j.chembiol.2026.08.011
  2. Front Mol Neurosci. 2026 ;19 1922816
    Rewriting the brain: m6A RNA methylation as an emerging epitranscriptomic regulator in major depressive disorder.
    Anuj K Verma, Hiroaki Mori, Bhaskar Roy, Yogesh Dwivedi.
      Activity-dependent gene regulation is fundamental to synaptic plasticity, and its disruption is increasingly recognized as a feature of major depressive disorder (MDD). Environmentally driven changes in gene expression can alter neural plasticity in corticolimbic brain regions, yet the post-transcriptional mechanisms linking environmental stress to maladaptive neuronal function remain incompletely understood. RNA epitranscriptomic regulation has recently emerged as an important layer of gene control, with N6-methyladenosine (m6A) representing the most abundant and dynamically reversible internal modification of mammalian mRNA. Widely present in the adult brain, m6A regulates RNA splicing, export, stability, localization, and translation, thereby shaping transcript fate and protein output. Although m6A RNA methylation has been studied extensively in other biological contexts, its contribution to MDD pathophysiology is only beginning to be defined. Current human evidence is primarily correlative, derived largely from bulk-tissue postmortem datasets, and should be considered hypothesis-generating until replicated in independent cohorts and validated with cell-type-resolved and mechanistic approaches. Emerging clinical and preclinical studies suggest that dysregulated m6A signaling may influence neurodevelopmental, neurocognitive, and stress-responsive pathways relevant to depression. By integrating environmental signals with transcriptomic regulation, m6A modification may represent a plausible epitranscriptomic mechanism governing synaptic plasticity in the depressed brain. In this review, we summarize the dynamic regulation of m6A RNA methylation in the brain, discuss its neurobiological functions, and critically evaluate its potential role in stress-related pathology and MDD.
    Keywords:  RNA modification; depression; epitranscriptomics; human brain; m6A RNA methylation; plasticity; stress
    DOI:  https://doi.org/10.3389/fnmol.2026.1922816
  3. J Virol. 2026 Sep 14. e0128226
    Viral control of translation: rise of the ribosome.
    Peter S Shen, Derek Walsh.
      Viruses have evolved a myriad of strategies to manipulate their host's protein synthesis machinery, studies of which uncovered many founding principles of translational control. Decades of research have established our now-extensive understanding of how these pathogens target the array of translation factors that recruit ribosomes and regulate scanning, start site selection, decoding, and termination. Meanwhile, the ribosome itself was largely regarded as a code-reading machine that lacks regulatory influence. Recent advances in cryo-electron microscopy and quantitative proteomics have upended this viewpoint by revealing the remarkable conformational and compositional plasticity that gives rise to functionally diverse and translationally selective ribosome populations in mammalian cells. Here, we discuss how viruses are once again at the forefront of this emerging field, often bypassing or rewiring host translation factors while directly controlling the ribosome's composition and intrinsic motions to selectively promote their non-canonical modes of translation. We offer cautionary perspectives on extra-ribosomal functions of ribosomal proteins, while highlighting the emergence of the 40S head domain as a dynamic platform targeted to control various translation processes, ranging from initiation to frameshifting, that expand viral coding capacity. Overall, we chart the rise of the ribosome from a passive player to an active regulatory hub at the center of viral translational control strategies.
    Keywords:  cryo-EM; ribosomal structure; ribosome; translational control; virus
    DOI:  https://doi.org/10.1128/jvi.01282-26
  4. Int J Mol Sci. 2026 Sep 05. pii: 7918. [Epub ahead of print]27(17):
    From Cellular Stress to Systemic Adaptation: The Circadian Clock and Stress Response at Cellular and Systemic Levels.
    Isabella Ivankovic, Hanuma Naik Ramavath, Ruifeng Ray Cao.
      The stress response is essential for cellular and organismal survival as it acts as a protective and adaptive mechanism to maintain homeostasis. At the organismal level, physical stressors induce responses in mammals that are mediated primarily by the hypothalamic-pituitary-adrenal (HPA) axis, which regulates glucocorticoid secretion. The HPA axis functions as a circadian-regulated, multi-oscillator system, in which the paraventricular nucleus, the pituitary, and the adrenal gland exhibit intrinsic rhythmicity while remaining coordinated by the output from the suprachiasmatic nucleus. Glucocorticoids act both as stress effectors and systemic zeitgebers that synchronize peripheral clocks. At the cellular level, cellular stressors are sensed by four protein kinases of eukaryotic translation initiation factor 2α (eIF2α) and activate the evolutionarily conserved integrated stress response (ISR), which converges on phosphorylation of Serine 51 on eIF2α. ISR signaling is temporally regulated by the circadian clock and controls time-of-day-dependent protein synthesis. In parallel, ISR pathways feed back onto the circadian clock through transcriptional, translational and epigenetic mechanisms, directly influencing core clock gene expression and stability of circadian oscillations. Physiological ISR activity supports circadian robustness and resetting, whereas excessive ISR activation dampens rhythmic gene expression and destabilizes behavioral rhythms. The current review summarizes recent advances in our understanding of the crosstalk mechanisms between the HPA axis, ISR, and the circadian clock to provide new insights into disease mechanisms and inform chronotherapeutic strategies to target dysregulated HPA and ISR activities and restore temporal homeostasis.
    Keywords:  ISR; circadian clock; glucocorticoid; stress
    DOI:  https://doi.org/10.3390/ijms27177918
  5. J Biol Chem. 2026 Sep 18. pii: S0021-9258(26)02452-X. [Epub ahead of print] 113580
    Medulloblastoma-associated mutations in the RNA helicase DDX3X/DED1 cause defects in the translational response to TORC1 inhibition.
    Akanksha Swarup, Ryan A Kuhs, Vanessa U Hardman, Kennedy L Howard, Shradha Subbaraman, Timothy A Bolger.
      Medulloblastoma is the most common pediatric brain cancer, but current treatments are largely non-specific, often causing developmental side effects. Genomic sequencing identified the RNA helicase DDX3X as one of the most frequently mutated genes in this cancer and a potential treatment target, yet its role in tumor progression remains elusive. Prior studies have indicated that the mutations cause specific defects in translation; however, both DDX3X and its yeast ortholog Ded1 have also been associated with cellular stress responses, suggesting that the contribution of the DDX3X mutations to medulloblastoma might result from defects in the translational response to stress. Building on our prior study that replicated the DDX3X mutations in yeast DED1 (ded1-mam), we examined the mutants' effects following TOR pathway inactivation. First, we demonstrated that ded1-mam displayed substantial rapamycin-resistant growth compared to wild-type cells. Additionally, similar to other ded1 mutants, the ded1-mam had increased protein abundance of Ded1 and the translation factor eIF4G1 under TOR inactivation. Notably, these differences did not result in increased bulk translation following rapamycin; rather, the growth phenotypes appeared to be driven by translation of specific mRNAs. Reporter assays demonstrated enhanced translation of mRNA with an unstructured 5' UTR in ded1-mam following TOR inhibition and a decrease in a structured reporter. Furthermore, known Ded1 target genes with relatively unstructured 5' UTRs showed upregulated protein levels in rapamycin. We hypothesize that mutant DDX3X selectively upregulates translation of unstructured, pro-growth transcripts while downregulating other structured transcripts, allowing tumor cells to bypass stress-induced growth controls and promoting medulloblastoma progression.
    Keywords:  RNA helicase; Saccharomyces cerevisiae; cancer; eukaryotic translation initiation; medulloblastoma; stress response; target of rapamycin (TOR)
    DOI:  https://doi.org/10.1016/j.jbc.2026.113580
  6. Cells. 2026 Sep 07. pii: 1623. [Epub ahead of print]15(17):
    Ivermectin Inhibits Stress Granule Clearance by Blocking the De Novo Synthesis of Hsp70 in Neuroblastoma Cells.
    Siwei Chu, Elizabeth P Anim, Reyhaneh Salehi-Tabar, John H White, Ursula Stochaj.
      Cytoplasmic stress granules (SGs) form in response to diverse insults; they are dismantled when the stress subsides. SG clearance is facilitated by molecular chaperones, nuclear transport factors, and other components. The anti-parasitic drug ivermectin inhibits nuclear trafficking and has potential anti-cancer activities. However, the molecular pathways that promote ivermectin's therapeutic actions are poorly understood. Our study defined the effects of ivermectin on stress recovery in human neuroblastoma and cervical carcinoma cells. We demonstrate that ivermectin interferes with SG disassembly in neuroblastoma cells. The delay of SG dissolution is accompanied by significant changes in the proteostasis network. Notably, ivermectin diminishes de novo protein synthesis in unstressed and stressed cells. During recovery, ivermectin reduces the abundance of hsp70 in neuroblastoma, but not in cervical carcinoma cells. Surprisingly, ivermectin has no effect on Hsf1 abundance and localization. Moreover, ivermectin does not diminish the levels of transcripts encoding hsp70. Bioorthogonal Non-Canonical Amino Acid Tagging revealed that ivermectin markedly reduces the stress-induced de novo synthesis of hsp70 in neuroblastoma cells. Taken together, ivermectin can derail stress responses by a unique mechanism that alters the translation of hsp70 mRNA and is determined by the cellular context. This information is directly relevant to ivermectin-based anti-cancer therapies.
    Keywords:  Bioorthogonal Non-Canonical Amino Acid Tagging; human cancer cells; ivermectin; molecular chaperones; stress granule; stress recovery; stress response
    DOI:  https://doi.org/10.3390/cells15171623
  7. Front Cell Dev Biol. 2026 ;14 1925311
    Selective remodeling of snoRNA and sdRNA biology in glioblastoma.
    Hongtao Yin, Meiying Mu, Zhuoqun Wang.
      Small nucleolar RNAs (snoRNAs) are best known as guide RNAs for ribosomal RNA modification, but accumulating evidence indicates that their biology extends beyond canonical ribosome maturation. Across GBM-specific and broader glioma studies, snoRNAs, snoRNA-derived RNAs (sdRNAs), and associated small nucleolar ribonucleoprotein components are emerging as regulators of malignant cell states. This review frames GBM-associated snoRNA and sdRNA alterations as a cell-biological remodeling process that links ribosome biogenesis, metabolic adaptation, treatment response, and extracellular-vesicle output. Across currently available GBM and broader glioma studies, tumor-restraining C/D-box snoRNAs, including SNORD76, SNORD47, SNORD44, and SNORD113-3, tend to be reduced, and restoration of several of these molecules suppresses malignant phenotypes in their respective experimental systems. Conversely, tumor-supporting snoRNA-associated activities, including the U3-PHAX-DNA-PKcs-TRIM24 complex, a U3-derived small RNA acting through ZBTB7A, and preprint-based H/ACA snoRNA/snoRNP activity involving dyskerin, are maintained, increased, or functionally co-opted in specific GBM-related contexts. These alterations converge on three recurrent cellular contexts: translational capacity, glucose and glycolipid metabolism, and survival under radiotherapy or temozolomide. Treatment-associated senescence may also reshape extracellular-vesicle snoRNA cargo, with SNORA49 detected in a small longitudinal plasma series, although this remains exploratory rather than a validated liquid-biopsy marker. We also emphasize the need to distinguish snoRNAs and sdRNAs from their SNHG host transcripts, because these molecular entities have distinct biogenesis and mechanisms. Together, these studies suggest a context-dependent pattern of snoRNA and sdRNA dysregulation across GBM and related glioma models, with the strength of evidence varying among individual molecular axes. SnoRNAs and sdRNAs should be viewed as an emerging regulatory layer in GBM rather than as established therapeutic targets. Future work should validate molecule-specific snoRNA and sdRNA axes in disease-relevant models and determine whether extracellular-vesicle snoRNAs provide reproducible readouts of treatment-associated cell states.
    Keywords:  extracellular vesicles; glioblastoma; liquid biopsy; ribosome biogenesis; small nucleolar RNA (snoRNA); snoRNA-derived RNA (sdRNA); therapy resistance; tumor metabolism
    DOI:  https://doi.org/10.3389/fcell.2026.1925311
  8. Cells. 2026 Sep 02. pii: 1596. [Epub ahead of print]15(17):
    The Paradox of Tau and RNA-Binding Proteins: How Adaptive Stress Granule Regulation Becomes Pathological with Aging.
    Benjamin Wolozin, Merci Best, Madhav Ellini, Yuran Ma, Sojung Bok, Dylan Hwang, Carolina Filipponi.
      RNA-binding proteins (RBPs) are a large class of proteins that form biological condensates to facilitate their functions. Chronic stress, such as occurs in neurodegenerative diseases, stimulates persistent accumulation of particular RBP condensates as part of the translational stress response, termed stress granules (SGs). These persistent SGs serve as a nidus for aggregation of RBPs to form pathologies that appear in neurodegenerative diseases, such as the occurrence of Tar DNA Binding Protein (TDP-43) in Amyotrophic Lateral Sclerosis. Many of the RBPs that accumulate in SGs are also associated with mutations that are linked to neurodegenerative diseases. The microtubule-associated protein tau is the major intracellular pathology that occurs in Alzheimer's disease. Tau is phosphorylated with stress, whereupon it functions to regulate SG biology; conversely, SGs serve as a crucible for the accumulation of toxic oligomeric tau. The regulation of stress by tau is an inherent part of biology that normally occurs during development and hibernation; however, with aging it becomes pathological, possibly because of the reduced proteostasis associated with aging.
    Keywords:  MAPT; RNA metabolism; TDP-43; biological condensate; liquid–liquid phase separation; membraneless organelle; oligomeric tau; protein aggregation; stress granule; translational stress response
    DOI:  https://doi.org/10.3390/cells15171596
  9. J Bioenerg Biomembr. 2026 Sep 14. pii: 52. [Epub ahead of print]58(1):
    Mitokines as bioenergetic stress signals in cardiovascular disease: mitochondrial communication, endocrine adaptation, and translational implications.
    Gino A Kurian.
      Cardiovascular disease is strongly influenced by mitochondrial dysfunction, yet how mitochondrial stress is communicated beyond the affected cell to coordinate systemic responses remains incompletely understood. Mitokines are stress-responsive signaling factors that link mitochondrial perturbation to cellular and interorgan adaptation. These include nuclear-encoded proteins such as fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15), as well as mitochondrial-derived peptides including Humanin and MOTS-c. This review critically examines mitokine regulation and signaling in the context of cardiovascular stress, with emphasis on mitochondrial unfolded protein response and integrated stress response pathways, receptor and downstream signaling mechanisms, and the functional divergence among major mitokines. Transient mitokine responses during physiological or metabolic challenge may support metabolic flexibility, cytoprotection, and stress adaptation, whereas persistent elevations of FGF21 and GDF15 in cardiovascular and cardiometabolic disease frequently accompany unresolved mitochondrial stress and adverse clinical phenotypes. Importantly, such associations do not establish that sustained mitokine signaling is itself maladaptive, and major mechanistic uncertainties remain, particularly for mitochondrial-derived peptides. We integrate these observations within a proposed "mitokine code" framework in which mitokine identity, relative patterns, temporal dynamics, and disease context may collectively provide information about mitochondrial stress and systemic adaptation. We further evaluate the potential and current limitations of mitokines as cardiovascular biomarkers and therapeutic targets. This framework positions mitokine signaling at the interface between mitochondrial dysfunction, systemic stress adaptation, and cardiovascular disease while identifying mechanistic and translational questions requiring prospective validation.
    Keywords:  Cardiovascular disease; Integrated stress response; Mitochondrial stress signaling; Mitochondrial unfolded protein response; Mitochondrial-derived peptides; Mitokines
    DOI:  https://doi.org/10.1007/s10863-026-10136-8
  10. Front Immunol. 2026 ;17 1878455
    N6-methyladenosine as a potential epitranscriptomic immune rheostat during SARS-CoV-2 infection.
    Xianfeng Hui, Shuoxiang Gao, Shihuan Ding, Mengyi Li, Xiaowei Tian.
      N6-methyladenosine (m6A), the most abundant internal RNA modification in eukaryotic cells, has emerged as a critical regulator of antiviral host defense. Increasing evidence indicates that m6A functions beyond conventional post-transcriptional regulation by dynamically coordinating the magnitude, timing, and duration of immune responses during viral infection. In SARS-CoV-2 infection, dysregulated antiviral immunity is characterized by delayed interferon activation together with sustained inflammatory responses, suggesting the existence of regulatory mechanisms that continuously calibrate immune signaling rather than simply switching it on or off. In this review, we propose the concept of m6A as a potential "epitranscriptomic immune rheostat," representing a conceptual framework in which m6A may fine-tune antiviral immunity through coordinated regulation of RNA stability, translational efficiency, and transcript turnover. We summarize how m6A shapes multiple layers of innate immune responses, including pattern recognition receptor sensing, type I interferon signaling, inflammatory buffering, and immune resolution. We further discuss emerging evidence suggesting that SARS-CoV-2 infection is associated with dynamic modulation of the m6A regulatory machinery and viral RNA methylation landscapes, while emphasizing that many mechanistic insights remain to be experimentally validated in SARS-CoV-2 models. In addition, we highlight the interplay between m6A regulation and immunometabolic remodeling, while distinguishing direct SARS-CoV-2 evidence from findings derived from other viral systems or broader m6A biology. Selected comparisons with Influenza A virus are discussed as complementary evidence to explore potentially conserved principles of m6A-mediated immune regulation among RNA viruses rather than as direct evidence for SARS-CoV-2 infection. Finally, we discuss the therapeutic implications of targeting the m6A regulatory network to recalibrate immune responses with temporal and cellular precision, while noting that current m6A-targeting strategies remain at the preclinical proof-of-concept stage and require further evaluation regarding specificity, safety, and translational feasibility. Collectively, this review provides a hypothesis-driven conceptual framework for understanding how m6A integrates RNA fate control with antiviral immunity and immunopathology during SARS-CoV-2 infection.
    Keywords:  N6-methylAdenosine (m6A); SARS-CoV-2; antiviral immunity; epitranscriptomic regulation; type I interferon signaling
    DOI:  https://doi.org/10.3389/fimmu.2026.1878455
  11. RNA. 2026 Sep 17. pii: rna.081017.126. [Epub ahead of print]
    Transcript-wide m6A methylation defines the efficiency of cap-independent translation initiation.
    Egor A Smolin, Andrey I Buyan, Dmitry N Lyabin, Anton A Buzdin, Ivan V Kulakovskiy, Irina A Eliseeva.
      N⁶-methyladenosine (m⁶A) plays an important role in translation control and, particularly, in cap-independent initiation. The impact of m⁶A is usually studied in the context of its location in the transcripts, but the global impact of m⁶A along mRNAs remains unclear. Here, we combined ribosome profiling under conditions of mTOR inhibition and m⁶A mapping to identify distinct subsets of mRNAs that differ in their sensitivity to the suppression of cap-dependent initiation. We found that the sensitivity strongly correlated with the total m⁶A methylation of the transcripts. Further, upon decreased mTOR activity, m⁶A methylation facilitated the enhanced association of mRNAs with components of the eIF4F complex. Thus, the efficiency of cap-independent translation initiation is primarily defined not by precise localization but by the total level of m⁶A methylation, and m⁶A has a compensatory role in maintaining translation when the canonical cap-dependent pathway is impaired. Our findings underscore the significance of contemplating global m⁶A methylation status as a pivotal element in translational control, particularly under stress or signaling perturbations.
    Keywords:  Ribo-Seq; cap-dependent initiation; m6A; mTOR inhibition
    DOI:  https://doi.org/10.1261/rna.081017.126
  12. Genes Dev. 2026 Sep 15.
    The hnRNPA1 D262V amyotrophic lateral sclerosis (ALS) mutation is linked to mitochondrial dysfunction.
    Yeon J Lee, Koning Shen, Andrew Dillin, Donald C Rio.
      Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by motor neuron loss and has been genetically linked to mutations in RNA-binding proteins. A mutation D262V in the RNA-binding protein hnRNPA1, found in a subset of ALS patients, causes widespread splicing pattern changes. Cells expressing this hnRNPA1 mutation exhibit aggregation, reduced proliferation, altered stress granules and abnormal neuronal growth. To further elucidate how a single amino acid substitution in a splicing factor might impact cell growth, we employed ribosome profiling to study translational dynamics across the transcriptome in hnRNPA1 mutant cells. Differential ribosome occupancy was observed for a small number of transcripts linked to synaptic organization and GTPase functions, as well as disrupted codon usage and a global stalling of translation. This downregulation of translation coincided with suppression of the mTOR/AKT signaling pathway. RNA splicing changes in transcripts from genes linked to cilia/cell projections, GTPase cycles and glutamate signaling were also observed. Importantly, major mitochondrial dysfunction and mitochondrial fragmentation were found in hnRNPA1 D262V mutant cells. Overall, this study demonstrates how a single amino acid change in an RNA binding protein can contribute to disrupting cell growth and mitochondrial function related to defects linked to neuronal death in ALS.
    Keywords:  amyotrophic lateral sclerosis (ALS); hnRNPA1; mitochondria
    DOI:  https://doi.org/10.1101/gad.353720.126
  13. Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00079-7. [Epub ahead of print]170 237-323
    Post-transcriptional regulation of erythropoiesis.
    Merlin Nithya Gnanapragasam, Raja Sundari Meenakshi Sundaram, Sarah E Adams, Rachael A White, Anita R Dhara, Parina N Patel, Sumayea B Mahmood Meem, Mahesh Ramamoorthy.
      Post-transcriptional mechanisms underlie various aspects of the erythropoiesis process, with a growing body of literature demonstrating its importance in the regulation of abundance, stability, and translational efficiency of the erythroid transcriptome. As the concerted actions of RNA binding proteins, alternative splicing, micro RNAs, long non-coding RNAs, and epitranscriptomic changes are increasingly uncovered, their importance in normal erythropoiesis and erythroid disorders are becoming better understood. Here, we systematically summarize the known post-transcriptional mechanisms in erythropoiesis, their perturbations in disease, and their potential in therapeutic applications.
    Keywords:  Alternate splicing; Early erythropoiesis; Epitranscriptomics; Erythroid terminal differentiation; Erythropoiesis; Hematopoiesis; Hemoglobin switching; Hemoglobin synthesis; Long non-coding RNAs; Micro RNAs; Post-transcriptional regulation; RNA binding protein; RNA modifications; RNA stability; Translational efficiency
    DOI:  https://doi.org/10.1016/bs.ctdb.2026.06.006
  14. Int J Mol Med. 2026 Nov;pii: 316. [Epub ahead of print]58(5):
    tRNA‑derived RNAs in hepatic diseases: From biological functions to clinical translation (Review).
    Yaotian Cai, Yifei Chen, Fuji Yang, Yongmin Yan, Ting Jiang.
      In recent years, with the deepening understanding of the significant role of small non‑coding RNAs in human health and diseases, transfer RNA‑derived RNAs (tsRNAs) have gradually become a research focus. Existing evidence shows that tsRNAs not only participate in the regulation of liver gene expression, translation and stress response, but may also act as signaling molecules to mediate inter‑organ communication. However, the specific pathological mechanism and clinical value in the occurrence and development of liver diseases remain unclear. Although tsRNAs show promising prospects as non‑invasive biomarkers and are expected to be used in the diagnosis of liver diseases, screening of therapeutic targets, drug delivery and regulation of enzyme activity, the methodological limitations at present and the differences in performance among different disease types and populations have significantly restricted their clinical translation. The present article systematically reviews the pathological roles of tsRNAs in various liver diseases, with a focus on elaborating their roles in tumor evolution, metabolic disorders and immune regulation. Their clinical application potential was also evaluated, methodological challenges were discussed, and future directions were proposed to advance tsRNA‑based clinical translation in hepatology.
    Keywords:  clinical translation; gut‑liver axis; hepatic diseases; non‑coding RNA; tRNA‑derived RNA
    DOI:  https://doi.org/10.3892/ijmm.2026.5987
  15. Cell. 2026 Sep 14. pii: S0092-8674(26)01004-4. [Epub ahead of print]
    Programmed ribosomal frameshifting triggers translational stress to promote viral replication.
    Audrey Xavier, Melinda Kolling, Ashley M Bourke, Thorsten Mosler, Cristian Prieto-Garcia, Emil Karaulanov, Michaela Reissland, Michel Tassetto, Damian Kim, Katleen Klaassen, Katharina Grikscheit, Emma Torbica, Verena Dederer, Jonas Busam, Rubina Kazi, Ruth Olmer, Srinivas Reddy Pallerla, Sebastian Mathea, Markus E Diefenbacher, Kathi Zarnack, Denisa Bojkova, Marek Widera, Ranen Aviner, Raul Andino, Sandra Ciesek, Ivan Dikic.
      Programmed ribosomal frameshifting (PRF) is a conserved viral strategy for expressing polyproteins from compact genomes. Although PRF is traditionally viewed as a structural mechanism, here we show that it functions as a regulatory signal that rewires host translation in favor of viral replication. A minimal SARS-CoV-2 PRF element is sufficient to activate the GCN2 arm of the integrated stress response (ISR) independently of the canonical ISR sensor ZAKα. This activation serves as a temporal switch during early infection to shut off host translation and is required for viral propagation in cells and human airway organoids. Proteomic and genetic screens identify DRG1 and IGF2BP3 as key mediators of PRF-induced GCN2 activation. We further show that this PRF-GCN2 axis is conserved in human immunodeficiency virus (HIV)-1 and West Nile virus, highlighting its broad relevance across RNA viruses. These findings reveal a sophisticated mechanism of viral translational control, highlighting PRF as a stress-inducing module that enhances viral replication.
    Keywords:  RNA virus; cellular stress; host-pathogen interactions; integrated stress response; programmed ribosomal frameshifting; ribosome collision; translation; virology
    DOI:  https://doi.org/10.1016/j.cell.2026.08.031
  16. Mol Cell Proteomics. 2026 Sep 18. pii: S1535-9476(26)00159-3. [Epub ahead of print] 101663
    Anagrelide remodels the PDE3A-SLFN12 interactome to associate with translation initiation machinery in cancer cell lines.
    Sami Salmikangas, Iina Lindholm, Nasrin Sultana, Nanna Merikoski, Kirsi Toivanen, Xiaonan Liu, Markku Varjosalo, Tom Böhling, Tiina Vesterinen, Harri Sihto.
      Phosphodiesterase 3A (PDE3A) modulators such as anagrelide induce complex formation between PDE3A and Schlafen 12 (SLFN12), selectively killing cancer cells that co-express both proteins. As PDE3A forms isoform- and cell type-specific signalosome complexes across multiple subcellular compartments, the effects of its modulation are expected to depend strongly on the surrounding protein interaction network. However, despite considerable pre-clinical and early clinical interest in PDE3A modulators, the cellular context in which these compounds act has remained poorly characterized. Using proximity-dependent biotinylation in two human cancer cell lines (SA-4, liposarcoma; HeLa, cervical adenocarcinoma), we mapped the interactomes of PDE3A, SLFN12, and the anagrelide-induced PDE3A-SLFN12 complex. Anagrelide induced 259 high-confidence interactions, most notably with ribosomal proteins and translation initiation factors, while suppressing 877 interactions, most prominently those associated with the proteasome, protein folding, and the ER membrane. Interactions were selectively induced with peripheral eukaryotic translation initiation factor 3 (eIF3) subunits eIF3A and eIF3B, while interactions with core eIF3 subunits eIF3H, eIF3L, and eIF3M were suppressed. These findings were validated by native co-immunoprecipitation across three cancer cell lines, and multiplex immunofluorescence confirmed accumulation and ribosomal redistribution of both PDE3A and SLFN12 following anagrelide treatment. AlphaFold modeling of the PDE3A-SLFN12 complex with a partial 43S pre-initiation complex predicted binding near eIF3B and the eIF2αβγ-tRNA ternary complex at the mRNA entry channel. By mapping the interactomes surrounding the drug-induced complex, our study provides important mechanistic context for how PDE3A modulators act within the cell. In our proposed model, anagrelide remodels the interactome of the PDE3A-SLFN12 complex, which relocalizes and accumulates near the mRNA entry channel of the 43S pre-initiation complex.
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101663
  17. Int J Nanomedicine. 2026 ;21 627556
    m6A-Targeted Cancer Therapy: Molecular Targets, Inhibitors, and Nanodelivery Strategies.
    Chenyu Li, Yuan Guo, Wenjun Jiang, Wei Xie, Yao Yao.
      m6A methylation modification, a widespread RNA post-transcriptional modification in eukaryotes, has been shown to play a crucial role in various biological processes, including gene expression regulation, cell proliferation and differentiation. By regulating RNA stability, translation, and degradation, m6A can influence the expression of oncogenic and tumor-suppressive transcripts and thereby contribute to cancer initiation and progression. In recent years, m6A-targeted therapy has emerged as a promising approach in cancer treatment, particularly with the development of m6A inhibitors and the integration of nano-delivery technologies, which have demonstrated significant therapeutic potential. This review summarizes recent advances in m6A-targeted cancer therapy, with emphasis on small-molecule inhibitors and RNA-based strategies targeting m6A regulators, and highlights their integration with nanocarriers, including lipid nanoparticles, polymeric nanoparticles, and extracellular vesicle-based systems, to improve drug stability, pharmacokinetic properties, tumor accumulation, and therapeutic selectivity. This integrated perspective highlights the emerging role of nanodelivery in advancing m6A-targeted cancer therapy and provides a framework for understanding its therapeutic potential. Despite these advances and promising preclinical evidence, the clinical translation of m6A-targeted therapies remains limited, with challenges related to drug specificity, delivery optimization, and the complexity of m6A regulatory networks. Finally, the article envisions future research directions, emphasizing the integration of interdisciplinary technologies, and predicts the broad prospects of m6A-targeted therapy in precision cancer treatment.
    Keywords:  inhibitor; m6A; nano-delivery; targeted therapy
    DOI:  https://doi.org/10.2147/IJN.S627556
  18. Curr Opin Immunol. 2026 Sep 17. pii: S0952-7915(26)00115-9. [Epub ahead of print]103 102838
    Cellular stress leading to epithelial cell dysfunction in Sjögren's syndrome.
    María-José Barrera, Isabel Castro, María-Julieta González.
      Cells are highly compartmentalized entities composed of membranous and nonmembranous structures, where organelles such as the endoplasmic reticulum (ER), Golgi apparatus, nucleus, mitochondria, lysosomes, peroxisomes, endosomes, and plasma membrane are organized. The plasma membrane physically and functionally connects the cytoplasm to the extracellular matrix, thereby generating a microenvironment that allows for the development of all the metabolic demands necessary to maintain cellular homeostasis. Salivary gland epithelial cells (SGECs, acinar and ductal) from Sjögren's syndrome (SS) patients undergo structural changes leading to loss of cell polarity and disrupted barrier function, resulting in severe alterations in the architecture of acini and ducts, which are sensed by their subcellular organelles as a condition of stress. The cellular stress response is a defensive mechanism that occurs when a cell loses its homeostasis due to internal or external factors. This response is organized into three sequential components: sensors detect the damage, the signaling cascade transmits the alarm, and effectors execute the adaptive action. One of these adaptive mechanisms is the integrated stress response, which is activated by various stress-inducing factors to adjust protein biosynthetic rates and redirect resources to mitigate stress and restore cellular homeostasis. Another adaptive mechanism is the unfolded protein response, which is activated by the accumulation of unfolded/misfolded proteins to restore ER proteostasis. Altered lysosomes, the Golgi apparatus, and mitochondria can also trigger stress. This review briefly discusses some cellular stress response pathways activated in SGECs, highlighting the perpetuating loop between inflammation and cellular stress in SS.
    DOI:  https://doi.org/10.1016/j.coi.2026.102838
  19. Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00081-5. [Epub ahead of print]170 1-48
    Ribosomal RNA transcription in normal and leukemic hematopoiesis.
    Jill A Henrich, Eleanor I Sams, Vikram R Paralkar.
      Hematopoiesis is governed by precisely coordinated transcriptional programs that balance hematopoietic stem cell (HSC) self-renewal with the ability to differentiate into multiple blood lineages. During normal hematopoiesis, cells maintain tight control over the level of ribosomal RNA (rRNA) transcription by RNA Polymerase I (Pol I) and over mature rRNA abundance (ribosomal subunits). Although the factors governing RNA Polymerase II (Pol II)-mediated gene expression and their roles in cell fate determination are well characterized, far less is known about the regulation of rRNA transcription and ribosome abundance. Little is known also about how ribosome numbers contribute to hematopoietic cell fate. This review summarizes current literature on the mechanisms by which hematopoietic cell types fine-tune rRNA transcription and ribosomal subunit abundance throughout cell fate trajectories, and how dysregulation of these processes contributes to acute myeloid leukemia (AML).
    Keywords:  Hematopoiesis; Leukemia; Nucleolus; RNA polymerase I (Pol I); Ribosomal DNA (rDNA); Ribosomal RNA (rRNA); Ribosome biogenesis; Ribosomes; rRNA transcription
    DOI:  https://doi.org/10.1016/bs.ctdb.2026.06.008
  20. Trends Plant Sci. 2026 Sep 15. pii: S1360-1385(26)00275-X. [Epub ahead of print]
    Advances of N6-methyladenosine RNA methylation in tree species.
    Huihui Wang, Huiyuan Wang, Xiaoxia Jin, Yusen Wang, Liangzhen Zhao, Bochen Jiang, Lianfeng Gu.
      N6-methyladenosine (m6A) is a pivotal post-transcriptional regulator in plants, but most mechanistic studies derive from arabidopsis (Arabidopsis thaliana) and annual crops. While core m6A machinery is conserved in plants, emerging studies in poplar, bamboo, and other tree species suggest that m6A modulates lignification and stress adaptation, likely reflecting perennial traits including long life cycle, secondary growth, seasonal developmental transitions. The major challenge of m6A research in trees is the shift from global m6A profiling to site-specific causal mechanism. New approaches like targets of RNA-binding proteins identified by editing, direct RNA sequencing, and dCas13-based programmable RNA epigenetic editors provide a practical resolution. In summary, this review extends m6A regulation from model plants to trees and highlights m6A's potential for improving tree traits.
    DOI:  https://doi.org/10.1016/j.tplants.2026.08.011
  21. Arch Gerontol Geriatr. 2026 Sep 05. pii: S0167-4943(26)00271-2. [Epub ahead of print]151 106402
    m(6)A RNA Methylation in aging and age-related diseases.
    Yuting Meng, Tianxing Liu, Minghui Ru, Rui Cai, Xinlan Liu, Wenting Li, Zixuan Xiao, Mengyi Guo, Jing Ma.
      Despite advances in prevention and treatment, aging and age-related diseases remain major causes of morbidity and mortality worldwide. N6-methyladenosine (m6A) is a prevalent internal modification of eukaryotic mRNA that regulates RNA splicing, export, stability, translation, and decay. In this comprehensive narrative review, we synthesize current evidence on the dynamic, tissue- and context-dependent remodeling of m6A during aging and in selected age-related pathologies. We emphasize how m6A functions as a post-transcriptional rheostat that complements canonical transcriptional and signaling pathways by controlling the fate of specific RNA transcripts. We discuss mechanistically supported roles of m6A in cellular senescence, the senescence-associated secretory phenotype, autophagy, oxidative stress, and organ dysfunction, while distinguishing established mechanisms from emerging or conflicting observations. We also critically evaluate the potential and current limitations of m6A regulators as biomarkers and therapeutic targets. By integrating evidence from human samples, animal models, and cellular systems, this review defines current knowledge gaps and outlines priorities for future mechanistic and translational research in aging.
    Keywords:  Cellular Senescence; aging-related diseases; m6A
    DOI:  https://doi.org/10.1016/j.archger.2026.106402
  22. ACS Omega. 2026 Sep 15. 11(36): 54424-54433
    Cryo-EM Structure of the 50S Ribosomal Subunit from the Phytopathogen Xanthomonas citri pv. glycines.
    Sombuddha Sengupta, Jyoti Tripathi, Nilantana Bandyopadhyay, Satyendra Gautam, Ruchi Anand.
      The Gram-negative phytopathogen, Xanthomonas citri pv. glycines (Xcg), is responsible for significant agricultural losses and has been shown to exhibit nutrient-dependent programmed cell death (PCD). Despite being an important pathogen, structural information on its ribosome, a key antibiotic target, remains limited. In this work, using cryogenic electron microscopy, we present the first reconstruction of the 50S ribosomal subunit from Xcg at 3 Å resolution. The structure reveals a conserved ribosomal RNA (rRNA) core architecture with certain species-specific features, such as truncations in the 23S rRNA that contribute to localized compaction. Our reconstruction also shows the Xcg 50S subunit to possess ribosomal protein bL25 in its "long-form" with an additional C-terminal domain, a feature typically associated with Gram-positive bacteria, suggesting an evolutionarily acquired adaptation for stress tolerance. These findings provide fundamental insights into the structural organization of the Xanthomonas 50S ribosomal subunit and help enable future structural and mechanistic interrogation of how ribosome-targeting antibiotics and small molecules directed at this phytopathogen may interact with its translational machinery.
    DOI:  https://doi.org/10.1021/acsomega.6c06206
  23. Int J Mol Sci. 2026 Sep 03. pii: 7868. [Epub ahead of print]27(17):
    METTL14-Mediated lncRNA MSTRG.292666.16 m6A Modification Promotes the Progression of Non-Small-Cell Lung Cancer Through the MAPK Pathway.
    Qinfang Deng, Hui Sun, Heyong Wang, Chenlei Cai, Xianxiu Ji, Qiyu Fang, Boxiong Xie, Songwen Zhou.
      Non-small-cell lung cancer (NSCLC) treatment is hampered by its complex pathogenesis and high heterogeneity. N6-methyladenosine (m6A) represents the most common post-transcriptional modification regulating RNA stability and function in eukaryotes. This methylation is catalyzed by methyltransferase complexes, with METTL14 being the core catalytic subunit. Abnormal expression of lncRNA MSTRG.292666.16 is related to poor prognosis of NSCLC. However, the mechanism by which it regulates NSCLC progression through m6A modification remains unclear. We employed cell function experiments, molecular mechanism analysis, RNA interaction experiments, and a nude mouse tumor model to explore the roles of METTL14-mediated MSTRG.292666.16 m6A modification in NSCLC and the potential MAPK signaling pathway involved. METTL14 was significantly upregulated in NSCLC cell lines and promoted m6A modification of MSTRG.292666.16 by forming a stable association with it. METTL14 knockdown significantly inhibited the viability, migration and invasion of A549 cells and promoted apoptosis, whereas MSTRG.292666.16 overexpression reversed these effects. Mechanistically, METTL14 upregulated the expression of MSTRG.292666.16 through m6A modification, thereby activating the MAPK pathway (manifested as elevated levels of MAPK8IP3 and p-ERK1/2). The use of a selective p38 MAPK inhibitor SB203580 stimulated the tumor-suppressive effect of METTL14 knockdown, whereas the activator U-46619 reversed it. In vivo experiments confirmed that METTL14 knockdown significantly inhibited tumor growth, whereas MSTRG.292666.16 overexpression partially restored the malignant phenotype of the tumor, which was associated with MAPK pathway activation. This study revealed that METTL14-dependent m6A modification of MSTRG.292666.16 may act as an upstream driver to activate the MAPK cascade and facilitate NSCLC progression. These findings clarify a key epitranscriptomic regulatory mechanism driving NSCLC development and offer preliminary molecular clues for exploring potential therapeutic targets in subsequent clinical NSCLC research.
    Keywords:  MAPK pathway; METTL14; lncRNA MSTRG.292666.16; m6A modification; non-small-cell lung cancer
    DOI:  https://doi.org/10.3390/ijms27177868
  24. Acta Pharmacol Sin. 2026 Sep 14.
    The RNA structural code: orchestrating gene expression and enabling precision therapies.
    Nan-Nan Fang, Qu-Bo Zhu.
      Following transcription, RNA undergoes hierarchical folding mediated by base pairing and long-range interactions, forming diverse dynamic structures such as local helices, loops, bulges, pseudoknots, G-quadruplexes, riboswitches, and higher-order conformations. These structures function as molecular switches that are recognized by RNA-binding proteins and regulatory factors, thereby precisely controlling the spatiotemporal dynamics of posttranscriptional gene expression. Emerging evidence indicates that aberrant RNA structural dynamics are closely associated with diverse human diseases. RNA-targeted therapeutic strategies, characterized by high specificity, programmability, and broad potential, have emerged as a promising next-generation therapeutic modality beyond conventional small-molecule and antibody-based therapies. Although current RNA-targeted approaches have focused primarily on gene silencing, strategies for enhancing endogenous gene expression are increasingly demonstrating substantial translational potential. In this review, we systematically summarize posttranscriptional gene regulation mechanisms mediated by RNA structural diversity, with a particular emphasis on the roles of RNA structures in alternative splicing, RNA localization and transport, translation, and RNA degradation. We further discuss recent advances, current challenges, and emerging clinical prospects of RNA-targeted therapeutic strategies in human diseases. Overall, this review provides a comprehensive overview of RNA structure‒function relationships and highlights their implications for precision medicine and the development of next-generation RNA-based therapeutics.
    Keywords:  RNA structure; RNA-targeted therapy; gene expression regulation; non-coding RNA; post-transcriptional control; precision medicine
    DOI:  https://doi.org/10.1038/s41401-026-01925-3
  25. BJC Rep. 2026 Sep 17. pii: 47. [Epub ahead of print]4(1):
    MiR-662 impairs C/D box snoRNA expression and rRNA 2'-O-ribose methylation marks.
    Charlotte Filossi, Caroline Isaac, Mariam Jaafar, Philippe Clézardin, Caroline Moyret-Lalle, Virginie Marcel, Margherita Puppo.
       BACKGROUND: MiR-662 overexpression has been reported to promote breast cancer metastatic progression and to impair the expression of genes encoding for proteins involved in translation, ribosome biogenesis and ribosome processing (Puppo et al., 2023); however, the relationship between miR-662 and the translational machinery was not further investigated at the time.
    METHODS: MiR-662 was overexpressed in MDA-MB-231-luc2 (NW1) human breast cancer cells. Global protein synthesis was analyzed using polysome profiles. Potential defects in rRNA 47S precursor biogenesis were evaluated by Northern blot. C/D box snoRNA (SNORD) expression was quantified by a medium-throughput RT-qPCR microfluidic dynamic array. rRNA 2'O-ribose methylation (2'Ome) was profiled using RiboMethSeq.
    RESULTS: No changes in rRNA synthesis, processing, or maturation were observed upon miR-662 overexpression. In contrast, a marked reduction in the ratio of polysomal to free ribosomal fractions was observed, indicating an impaired mRNA engagement into translation. Interestingly, a drastic decrease in SNORD levels (but not of their host genes) and a global decrease in rRNA 2'Ome was observed upon miR-662 overexpression.
    CONCLUSIONS: The involvement of miRNAs in snoRNA-induced modulation in rRNA epitranscriptomic marks might be a novel mechanism of fine regulation of the ribosome composition with possible repercussions on breast cancer metastatic progression.
    DOI:  https://doi.org/10.1038/s44276-026-00247-5
  26. Neurotox Res. 2026 Sep 12. pii: 53. [Epub ahead of print]44(5):
    Genetics of α-Synuclein: The Prime Pathological Player of Parkinson's Disease.
    Tanveera Rounaque Sarhadi, Neha Joshi, Atchaya Raveendran, Janhavee Shirish Panse, Shirisha Nagotu.
      Parkinson's disease is a complex neurodegenerative disorder that results from the interplay of genetic, environmental, and age-associated factors. The characteristic pathological feature of the disease is the presence of aggregated forms of the intrinsically disordered protein α-synuclein. Protein aggregates eventually form Lewy bodies, which are associated with the death of dopaminergic neurons. Elevated expression, mutations in the coding sequence, increased misfolding, and decreased degradation contribute to the aggregation of α-synuclein, associated with the disease. Mutations in the SNCA gene, which encodes α-synuclein, are predominantly associated with the familial form of the disease. The majority of the identified mutations are located in the N-terminal region of the protein and are associated with either early- or late-onset of the disease. Studies using model organisms, cell lines, and animal models identified several cellular effects associated with mutated forms of the protein. In addition, the clinical phenotypes of the disease in patients with different mutations vary in intensity. Interestingly, although each mutation is associated with the disease, the resulting α-synuclein aggregation rate and effect on cellular pathways are variable. In this review, we aim to summarize these interesting alterations in the protein and the associated pathophysiology of the disease following a single amino acid change.
    Keywords:  Aggregation; Mutation; Organelle; Parkinson’s disease; α-synuclein
    DOI:  https://doi.org/10.1007/s12640-026-00827-w
  27. Med Gas Res. 2027 Jan 01. 17(1): 129-138
    Nitric oxide signaling and mitophagy in Parkinson's disease: implications for aerobic exercise-related neuroprotection.
    Yang Zhou, Yongliang Wu.
      Parkinson's disease is strongly associated with mitochondrial dysfunction and impaired mitochondrial quality control, including defective mitophagy. Aerobic exercise is increasingly recognized as a safe and accessible intervention that can improve motor and non-motor outcomes in Parkinson's disease and may also engage mechanisms relevant to disease modification. In this review, we propose a context-dependent framework in which aerobic exercise reshapes nitric oxide signaling toward a more adaptive profile, characterized by relatively moderate, transient, and spatially restricted nitric oxide bioactivity, and we discuss how this shift may influence mitochondrial biogenesis, mitophagy initiation, and autophagic flux regulation. Rather than treating nitric oxide as uniformly protective or deleterious, we argue that its biological effects in Parkinson's disease depend on source, concentration, duration, subcellular localization, cellular target, and surrounding redox milieu. However, direct evidence that exercise-derived nitric oxide activates these pathways in Parkinson's disease-relevant neural tissue is still limited. We further highlight major translational gaps, including cell-type and brain-region heterogeneity, incomplete definition of exercise dose-response relationships, and the lack of validated in vivo biomarkers of neuronal mitophagy and nitric oxide dynamics in patients with Parkinson's disease. Overall, aerobic exercise is a plausible modulator of mitophagy-related pathways in Parkinson's disease, and nitric oxide is a credible contributor to this effect; however, the current evidence supports a multi-node, context-dependent model rather than a simple linear mechanism.
    Keywords:  PINK1/Parkin pathway; Parkinson’s disease; S-nitrosylation; aerobic exercise; mitochondrial dysfunction; mitochondrial quality control; mitophagy; neuroprotection; nitric oxide; oxidative stress
    DOI:  https://doi.org/10.4103/mgr.MEDGASRES-D-26-00008
  28. Mol Biol Cell. 2026 Sep 16. mbcE25080391
    Regulation of TIPIN and replication fork dynamics by USP37.
    Benjamin R Stromberg, Luke Scarberry, Irene S Cho, Matthew K Summers.
      The deubiquitinating enzyme, USP37, is associated with control of replication and the replication stress response. Cells with oncogene-induced replication stress harbor elevated levels of USP37 and are more sensitive to its loss. These cells experience increased replication stress and delayed progression of the replication fork in the absence of USP37. Consistent with these observations, we find that USP37-deficient cells more frequently fail to restart stalled forks and that these forks are more susceptible to nuclease activity. Underlying these phenomena, we show that USP37 resides at the replication fork and associates with the replisome where it is able to act on TIPIN to promote its stable association with chromatin. These findings suggest the regulation of proteins at the replication fork contributes to fork function and underlies the requirement of cancer cells for USP37.
    DOI:  https://doi.org/10.1091/mbc.E25-08-0391
  29. Am J Med Genet A. 2026 Sep 17.
    L-Cysteine and N-Acetylcysteine Supplementation Improves Clinical Outcome in a Patient With COXPD10.
    Nishitha R Pillai, Sara A Elsbecker, Grace Bronken McCarthy, Kaitlin Weisshappel, Peter Karachunski, Fernando Scaglia.
      MTO1 is a nuclear gene that encodes a mitochondrial protein essential for modifying mitochondrial transfer RNAs (tRNAs) and stabilizing codon-anticodon interactions to ensure accurate and efficient mitochondrial protein synthesis and oxidative phosphorylation. Mitochondrial tRNA translation optimization 1 (MTO1) plays an important role in the mitochondrial tRNA taurinomethylation modification by using the amino acid taurine, obtained from cysteine metabolism, at the wobble position U34 of the anticodon loop. Biallelic pathogenic variants in MTO1 cause combined oxidative phosphorylation deficiency 10 (COXPD10) (OMIM#614702). In the severe end of the spectrum, COXPD10 is characterized by infantile-onset hypertrophic cardiomyopathy and lactic acidosis with perinatal mortality when associated with nonsense and frameshift variants. The extra cardiac phenotypes include muscle hypotonia, feeding difficulties, psychomotor delay, optic atrophy, encephalopathy, and seizures. Currently, there is no targeted treatment for this condition aside from supportive care. Herein, we report a 22-month-old child, diagnosed early with a genotype predictive of severe COXPD10, who was initiated on treatment with L-cysteine and N-acetylcysteine (NAC) early in life and did not develop cardiac manifestations. This outcome suggests a potential benefit and improved clinical outcome with early disease-specific treatment initiation.
    Keywords:   MTO1 ; COXPD10; L‐cysteine; NAC; N‐acetylcysteine; cardiomyopathy; combined oxidative phosphorylation deficiency 10; cysteine
    DOI:  https://doi.org/10.1002/ajmg.a.70299
  30. Commun Biol. 2026 Sep 17. pii: 1215. [Epub ahead of print]9(1):
    N4BP1 uses tandem KH domains to associate with EDC4 and mRNA decapping factors in P-bodies.
    Paweł Piłat, Ankur Garg, Udo Heinemann, Mateusz Wilamowski, Jolanta Jura.
      Processing bodies (P-bodies) are cytoplasmic, non-membrane-bound structures involved in mRNA decay. EDC4 serves as a key scaffold for the decapping complex within P-bodies. Here, we demonstrate that N4BP1 interacts with EDC4, as well as with DCP1A, DCP2, and XRN1 - key components of 5'-cap hydrolysis. Endogenous N4BP1 colocalizes with EDC4 in P-bodies, requiring both of its KH domains. Structural analysis revealed that N4BP1 contains a type-I KH fold but lacks the canonical GXXG motif required for single-stranded RNA binding. Deletion or mutation of KH domains non-canonical GXXG motifs disrupts the N4BP1-EDC4 complex. N4BP1 reduces HIV-1 transcript levels independently of its P-body localization or association with decapping components, implying the involvement of other host factors in regulating viral mRNAs. Similarly, for N4PB1-dependend negative regulation of endogenous transcripts in HaCaT keratinocytes, EDC4 is not essential. For both HIV-1 and endogenous transcripts, the reduction is associated with the activity of the NYN domain.
    DOI:  https://doi.org/10.1038/s42003-026-10938-x
  31. Front Cell Dev Biol. 2026 ;14 1879681
    Target, silence, replace: a review on RNA-based drugs in modern medicine.
    Poonam Mundlia, Suraj Pratap Singh, Pritiman Pothal, Tanya Thakur, Reema Kathuria, Sudhanshu Maurya, Akanksha Sharma, Honey Goel, Ankur Pandey, Pavitra Ranawat, Gurpal Singh, Ravi Pratap Barnwal.
      RNA therapies have evolved into a revolutionary approach in contemporary medicine for treating various diseases by directly targeting RNA molecules engaged in disease pathogenesis. These therapeutic agents regulate biological processes through diverse mechanisms, including modulation of RNA function and gene expression. Medical applications of RNA are greatly enhanced by its structure, adaptability, and capacity for targeted binding. Among these traits is its ability to bind to certain molecules unique to those chemicals. RNA-based treatments have emerged from advancements in the production, modification, and cellular transport of RNA molecules. Several RNA drugs have been approved whereas some are under trial for few diseases. RNA therapeutics can function at the level of RNAs, DNAs and proteins. The evolution of mRNA vaccines during the COVID-19 epidemic emphasizes the exciting potential of RNA therapies in the treatment of diseases. This article provides a comprehensive overview of the several forms of RNA therapies, including small-interfering RNA (siRNA), messenger RNA (mRNA), and antisense-oligonucleotides (ASOs), together with information on their action mechanisms and delivery strategies that improve cellular absorption and shield RNA molecules from degradation. Further, CRISPR-based editing of the genome can be employed for modification of target RNA sequences for various disorders. Development of RNA aptamers have also been identified as pivotal RNA-therapeutic candidate. Additionally, we have explained mechanistic details and examples of drugs approved for RNA therapy. Emphasizing their potential to enhance patient outcomes and fulfil unmet medical requirements, we also highlight the clinical development of RNA therapies in treating cancer and other infectious diseases.
    Keywords:  RNA interference; RNA therapeutics; antisense oligonucleotides; aptamer; messenger RNA; nanoparticle delivery
    DOI:  https://doi.org/10.3389/fcell.2026.1879681
  32. J Virol. 2026 Sep 17. e0128426
    Regulation and function of the HPV16 CircE7 RNA.
    Eunice E Lee, Yihui Huang, Eleanor Dowell, Kaitlyn Walsh, Calvin Hosler, Austin Witt, Odera Ifeacho, Doreen Palsgrove, Andrew Day, Claire James, Richard C Wang.
      High-risk human papillomaviruses (HPV), including HPV16, produce circular RNA that encompasses the E7 oncogene (circE7). CircE7 can be detected in HPV16-positive cells and tumors, is preferentially localized to the cytoplasm, is N6-methyladenosine (m6A)-modified, and can be translated into the E7 oncoprotein. Here, we explored the regulation and function of circE7. Mutation of m6A motifs flanking the backsplice junction revealed a single m6A motif to be essential for circE7 formation. Mutation of this m6A motif promoted linear splicing of the E6*I splice site (226^409), suggesting that linear and circular E7 splicing are inversely regulated. Additionally, mutation of an IRES-like motif in circE7 significantly decreased E7 protein expression, without having significant effects on circE7 RNA levels. Knockdown of YTHDC1, but not other m6A-binding proteins, decreased both circE7 RNA and protein expression. BaseScope ISH was used to confirm the expression of circE7 in head and neck squamous cell carcinoma cell lines and tumors. Using both qRT-PCR and BaseScope ISH, we found that serum and amino acid starvation significantly increased circE7. Finally, we generated an HPV16 genome with mutations in the circE7 m6A motif (Mut2). Stable transduction of primary keratinocytes with Mut2 confirmed the loss of circE7 and increased expression of E6*I. The Mut2 HPV16 genome exhibited significantly decreased viral replication but an increased ability to transform primary keratinocytes. Our studies reveal that the precise regulation of circE7 and E6*I by m6A is critical for the ability of HPV16 to infect and transform keratinocytes.IMPORTANCEHigh-risk human papillomaviruses (HPVs), such as HPV16, must carefully control how much E6 and E7 proteins they make. This study shows that HPV16 toggles a single chemical tag on the viral RNA (an m⁶A mark) to control the production of early region RNAs, including a circular RNA called circE7. The same site coordinately regulates splicing of the E6*I isoform. CircE7 uses m⁶A-binding proteins to control its production and a specific sequence to promote its translation. It is present in HPV-positive cancers and can respond to nutrient starvation. Regulation of circE7 through this m6A site also impacted viral replication and transformation capacity, indicating that this regulatory mechanism is critical for HPV biology.
    Keywords:  RNA splicing; carcinogenesis; circular RNA; head and neck cancer; internal ribosome entry site; m6A; papillomavirus; transformation; translation
    DOI:  https://doi.org/10.1128/jvi.01284-26
  33. Plant Physiol Biochem. 2026 Sep 15. pii: S0981-9428(26)00740-0. [Epub ahead of print]238 111754
    Human m6A demethylase FTO modulates the flowering time of tomato plants under low-temperature stress.
    Umme Amara, Ying Yang, Longyushu Li, Long Zhang, Yiran Heng, Jing Cai, Jiaju Tao, Jing Dong, Hunseung Kang, Tao Xu.
      N6-methyladenosine (m6A) RNA modification plays an important role in plant development and environmental stress responses. However, whether m6A demethylation modulates flowering under low-temperature (LT) stress in tomatoes remains unclear. Here, we investigated whether ectopic expression of FTO, a well-characterized human m6A demethylase, influences flowering and post-transcriptional behaviour in tomato (Solanum lycopersicum) under LT conditions. Flowering of transgenic tomato plants expressing FTO was analyzed under LT and normal conditions (NC), and the impacts of FTO on transcripts-specific m6A level, mRNA stability and splicing efficiency of flowering-related genes were evaluated using RT-qPCR, LC-MS/MS, m6A-IP-qPCR, and RNA decay and splicing analyses. FTO-expressing plants exhibited accelerated flowering specifically under LT, whereas no significant differences were observed under normal growth conditions. This phenotype was accompanied by increased expression of positive floral regulators (SlMC, SlFCA, and SlJ2) and decreased expression of negative regulators (SlSVP, SlSP, and SlTMF) under LT conditions. Notably, these expression changes were associated with altered mRNA stability, with positive regulators showing increased stability and negative regulators showing reduced stability under LT conditions. m6A-IP-qPCR analysis indicated reduced m6A enrichment in these selected transcripts in FTO-expressing plants. In addition to effects on mRNA stability, FTO expression was associated with changes in the splicing efficiency of SlMC transcripts. Collectively, our findings indicate that human FTO functions as an mRNA m6A demethylase in tomatoes and is associated with altered RNA regulatory processes under LT conditions. These findings suggest that m6A-mediated post-transcriptional regulation contributes to stress-induced flowering plasticity under LT conditions, rather than direct activation of canonical flowering pathways.
    Keywords:  Abiotic stress; FTO; Low-temperature; RNA methylation; Tomato; m(6)A eraser
    DOI:  https://doi.org/10.1016/j.plaphy.2026.111754
  34. Amino Acids. 2026 Aug 30. pii: 48. [Epub ahead of print]58(1):
    Polyamine metabolic enzyme SAT1 remodels the neuronal transcriptome and rescues α-synuclein toxicity in Drosophila.
    Zoya R Bangash, Hiroyoshi Matsui, Bedri Ranxhi, Sokol V Todi, Peter A LeWitt, Wei-Ling Tsou.
      Polyamine homeostasis is tightly regulated by interconversion and catabolic pathways and has been increasingly implicated in neurodegenerative disorders, including Parkinson's disease (PD), where accumulation of α-synuclein (α-Syn) perturbs neuronal homeostasis. Spermidine/spermine N¹-acetyltransferase 1 (SAT1) occupies a central position in polyamine interconversion, and alterations in SAT1 activity have been linked to α-Syn toxicity and PD-related neuropathology. To investigate how SAT1 activity influences α-Syn-associated neurodegeneration, we employed a Drosophila model of neuronal α-Syn expression. SAT1 overexpression reduced α-Syn protein levels, altered its subcellular distribution within the brain, and mitigated α-Syn-induced lifespan shortening. Transcriptomic analyses showed that SAT1 modulates stress-associated gene expression in the α-Syn background, including attenuation of chaperone and ubiquitin-related responses and coordinated changes in pathways linked to mitochondrial function and amino acid metabolism. SAT1 co-expression partially restored α-Syn-associated alterations in genes involved in mitochondrial quality control, including USP30, Uch-L5R, RNF185, and the mitochondrial ornithine carrier SLC25A15. At the protein level, SAT1 increased mitochondrial-associated signal, enhanced LC3 association with mitochondrial compartments, restored LC3-II/LC3-I ratios in mitochondrial fractions, and reduced mitochondrial accumulation of α-Syn. Functional analyses further showed that SAT1 increased steady-state ATP levels and attenuated the ATP depletion induced by α-Syn expression. These findings indicate that SAT1 activity is associated with reduced α-Syn toxicity and preservation of mitochondrial homeostasis during α-Syn-associated stress.
    Keywords:  Autophagy; Mitochondrial quality control; Neurodegeneration; Parkinson’s disease; Polyamine interconversion; RNA sequencing
    DOI:  https://doi.org/10.1007/s00726-026-03544-y
  35. Front Cell Dev Biol. 2026 ;14 1928071
    RNA m6A modification-regulated ferroptosis in cancer: mechanism and therapeutic potential.
    Qingmiao Shi, Yangni Li, Chaonan Guan.
      Ferroptosis, an iron-dependent form of regulated cell death, is increasingly recognized as a context-dependent therapeutic vulnerability in cancer, particularly as malignant cells adapt to oxidative, metabolic, and therapy-induced stresses. As a prevalent and reversible epitranscriptomic modification, RNA N6-methyladenosine (m6A) modification orchestrates RNA stability, translation, splicing and decay; consequently, its dysregulation contributes to cancer progression and therapeutic resistance. The intersection of m6A regulation and ferroptosis is therefore biologically important because many ferroptosis threshold genes are short-lived, stress-responsive transcripts controlled by writers, erasers, readers and RNA-binding proteins. This review synthesizes empirical evidence elucidating how m6A regulators remodel cystine import, GPX4-dependent antioxidant defense, FSP1 signaling, lipid metabolism, iron handling, autophagy and tumor-microenvironmental communication. We organize the evidence by regulatory layer rather than cancer type, covering writer-mediated deposition, reader and RNA-binding protein recognition, eraser-dependent demethylation, non-coding RNA and exosomal regulation, and downstream ferroptosis modules. We further discuss how this axis contributes to radiotherapy, chemotherapy, targeted-therapy resistance and ferroptosis-sensitizing combinations. Although m6A-ferroptosis crosstalk offers promising biomarker and therapeutic opportunities, translation requires transcript-level validation, standardized ferroptosis assays, tumor-selective delivery and clinically meaningful patient stratification. A deeper and more precise integration of epitranscriptomics with ferroptosis biology holds the potential to transform stress-adaptive RNA circuits into actionable vulnerabilities for precision cancer therapy.
    Keywords:  RNA N6-methyladenosine; cancer; epitranscriptomics; ferroptosis; therapy resistance
    DOI:  https://doi.org/10.3389/fcell.2026.1928071
  36. Mol Med Rep. 2026 Nov;pii: 309. [Epub ahead of print]34(5):
    Mitochondria‑associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review).
    Shilong Meng, Xinlei Fu, Yawei Xu, Zhiliang Peng, Xu Zhang, Yanguang Cao, Binbin Tang, Xiaolin Shi, Kang Liu.
      Mitochondria‑associated endoplasmic reticulum membranes (MAMs) are specialized endoplasmic reticulum (ER) membrane domains at ER‑mitochondrial contact sites that coordinate Ca²+ transfer, lipid exchange, mitochondrial quality control and cellular stress responses. In osteoporosis, intervertebral disc degeneration, osteoarthritis and sarcopenia/skeletal muscle atrophy, altered ER‑mitochondrial communication has been linked to recurrent disturbances in Ca²+ homeostasis, mitochondrial function, ER stress, inflammatory signaling and cell fate. However, evidence for MAM involvement varies markedly in directness and biological context. This narrative review compares these evidence patterns and their therapeutic implications across degenerative musculoskeletal disorders. Direct structural and causal evidence is most developed in intervertebral disc degeneration and selected osteoarthritis models; osteoporosis is supported mainly by studies of MAM‑associated regulators and functional pathways, whereas sarcopenia‑specific mechanisms remain largely informed by aging muscle and related experimental models. The direction and consequences of contact remodeling also vary with cell type, metabolic state and disease stage, arguing against a uniform gain‑ or loss‑of‑contact model. Interventions targeting contact‑site regulators or MAM‑related Ca²+ and mitochondrial pathways have shown preclinical benefit, but MAM‑specific target engagement and human validation remain limited. Progress will require paired structural and functional assessment together with validation in clinically characterized human tissues and patient‑derived systems.
    Keywords:  ER‑mitochondrial contacts; endoplasmic reticulum stress; ferroptosis; mitochondrial dysfunction; mitochondria‑associated endoplasmic reticulum membranes; musculoskeletal degeneration; organelle communication
    DOI:  https://doi.org/10.3892/mmr.2026.14020
  37. Appl Biochem Biotechnol. 2026 Sep 17.
    RBM15 Contributes to Bladder Carcinoma Progression via m6A-dependent Stabilization of IFI6 mRNA.
    Hanchao Zhang, Yue Yang, Zhengdao Liu, Faliang Zhao, Guobiao Liang.
      Bladder carcinoma (BLCA) is a prevalent urological malignancy with limited therapeutic options. Interferon α inducible protein 6 (IFI6) is implicated in various cancers, but its role in BLCA remains unexplored. qRT-PCR and western blot were used for expression analysis. Functional assays (cell counting kit 8, 5-ethynyl-2'-deoxyuridine staining, flow cytometry, wound healing, transwell, and 2', 7'-dichlorodihydrofluorescein diacetate fluorescent probe) and xenograft mouse models were used to assess the effects of IFI6 and RNA binding motif protein 15 (RBM15) on BLCA. The N6-methyladenosine (m6A) modification sites on IFI6 were predicted by the sequence-based RNA adenosine methylation site predictor website and the combination of RBM15 was validated via RNA-binding proteins site prediction websites, methylated RNA immunoprecipitation, Actinomycin D, dual-luciferase reporter assay, and RNA binding protein immunoprecipitation assays. IFI6 was elevated in BLCA tissues and cells. IFI6 knockdown could inhibit proliferation, migration, and invasion, while enhancing apoptosis and oxidative stress of BLCA cells. Besides, silencing of IFI6 blocked BLCA tumor growth. RBM15, an m6A writer, directly bound IFI6 to stabilize its mRNA through m6A modification. Rescue experiments confirmed that IFI6 overexpression reversed RBM15 knockdown-mediated the suppression effect on BLCA cell proliferation and metastasis. Our study identifies that RBM15/IFI6 axis is a novel m6A-dependent pathway driving BLCA progression, offering a potential therapeutic target for BLCA.
    Keywords:  Bladder carcinoma; Interferon α inducible protein 6; N6-methyladenosine; RNA binding motif protein 15
    DOI:  https://doi.org/10.1007/s12010-026-05924-2
  38. Int J Biometeorol. 2026 Sep 17. pii: 259. [Epub ahead of print]70(10):
    Transcriptomic analysis reveals physiological adaptations and immune system modulation in Romanian Holstein cattle during heat stress exposure.
    Daniela Elena Ilie, Alexandru Eugeniu Mizeranschi, Madalina Mincu-Iorga, Ludovic Toma Cziszter, Ioana Nicolae, Dinu Gavojdian.
      Heat stress represents a significant impairment to productivity, health, and reproductive efficiency of dairy cattle globally. The present study aimed to investigate genes and molecular mechanisms involved in physiological response to heat stress in Romanian Holstein dairy cows, by conducting a whole-blood transcriptomic and bioinformatics analysis. RNA sequencing (RNA-Seq) was performed on samples collected from seven multiparous Romanian Holstein cows under both heat stress (HS, average temperature-humidity index -THI of 77.5) and thermoneutral (TN, average THI of 48.3) conditions. A total of 487 (447 downregulated and 40 upregulated) significantly (|log2FC| ≥ 1 and adjusted p-value ≤ 0.05) differentially expressed genes (DEGs) were identified, during HS exposure compared to TN conditions. Downregulated genes were primarily associated with crucial physiological functions, including immune responses, inflammation, and metabolic pathways, all of which directly influence milk production, health and reproductive efficiency. Upregulated genes revealed active cellular protection mechanisms, notably heat shock proteins (HSPs), and a pronounced activation of the innate immune and antiviral defense responses, alongside metabolic adjustments and complex reproductive responses. Significant enrichment in pathways in response to heat stress included viral defense and lysosomal activity, suggesting an intensified cellular catabolism under thermal stress. In conclusion, Romanian Holstein cattle exhibit a complex, integrated molecular response to heat stress, characterized by a survival-oriented shift in gene expression. These findings provide detailed molecular insights into the physiological challenges faced by dairy cattle during heat stress exposure.
    Keywords:  Dairy cattle; Gene expression; Heat stress; Romanian Holstein; Transcriptome analysis
    DOI:  https://doi.org/10.1007/s00484-026-03306-1
  39. Nucleic Acids Res. 2026 Sep 07. pii: gkag877. [Epub ahead of print]54(17):
    Zinc-dependent turnover of ZIP3 transporter mRNA by trypanosome ZNK1.
    Teresa Leão, Anna Trenaman, Michele Tinti, Gustavo Bravo Ruiz, Idálio J Viegas, Luisa M Figueiredo, Margarida Duarte, Ana Maria Tomás, David Horn.
      Like other cells, parasitic and other trypanosomatids sense Zn2+ and regulate Zn2+ transport, but the mechanisms involved remained unknown. Here, we identify a trypanosome RNA-binding protein that specifically eliminates ZIP3 transporter mRNA in Zn2+-replete conditions. We first demonstrate that Trypanosoma brucei ZIP3 mRNA abundance is subject to 3'-untranslated region (3'-UTR) and Zn2+-dependent negative control. A genome-wide RNA interference library screen, using a reporter associated with the ZIP3 3'-UTR, identifies Tb927.11.9510 as a candidate Zn2+-sensor, and we name this protein Zinc Nuclear Knuckles 1 (ZNK1) since it localizes to the nucleus and contains several Zn2+-knuckle motifs. ZNK1 is conserved among trypanosomatids, and a PIN domain suggests a ribonuclease-based mechanism. We use Cas9-editing to knockout ZNK1 and observe specific accumulation of ZIP3 transcripts, and increased intracellular Zn2+, in znk1 null cells. We validate ZNK1 as a ZIP3 3'-UTR-dependent negative regulator and identify a GU-repeat motif in the ZIP3 3'-UTR that is predictive of ZNK1-based negative control. In conclusion, ZNK1 eliminates ZIP3 transporter mRNA in a Zn2+-dependent manner. We suggest that trypanosomatid ZNK1 is a highly selective zinc finger nuclease that binds GU-repeat motifs within ZIP3 3'-UTRs and degrades Zn2+ transporter mRNA only when the tandem sensor knuckle modules are coordinated with Zn2+.
    DOI:  https://doi.org/10.1093/nar/gkag877
  40. Int J Mol Sci. 2026 Aug 22. pii: 7516. [Epub ahead of print]27(17):
    Deletion Analysis of Phase Separation, Amyloid Formation and Prion Propagation by the Intrinsically Disordered Region of Yeast Sup35 Protein.
    Anastasia V Grizel, Natalia A Gorsheneva, Ismat Jahan Anee, Kristupas Paulius, Konstantin Y Kulichikhin, Aleksandr A Rubel, Yury O Chernoff.
      Protein intrinsically disordered regions (IDRs) play important biological roles despite lacking stable structures. IDRs drive the formation of both biomolecular condensates via liquid-liquid phase separation (LLPS) and solid fibrous amyloid aggregates. Amyloids can be pathogenic and may exhibit self-perpetuating (prion) properties. Relationships between LLPS and the amyloid-forming and prion-propagating abilities of IDRs remain poorly understood. The N-proximal IDR of the yeast translation termination factor eRF3 (Sup35) can form both liquid condensates and heritable amyloid-based prions and serves as a powerful model for investigating these phenomena due to the availability of simple phenotypic, cytological and biochemical assays. Deletion analysis demonstrates that the N-proximal prion domain (Sup35N) of Sup35 is sufficient for chaperone-dependent prion propagation and that various regions of this domain show differential impacts on LLPS, amyloid aggregation, and prion inheritance. Specifically, the N-terminal NQ-rich stretch and the region of oligopeptide repeats are the most important contributors to the LLPS and formation of amyloid fibrils, while oligopeptide repeats and the C-terminal region of Sup35N are crucial for prion inheritance. Contrary to previous reports, the NQ-rich stretch is not required for prion formation and inheritance in yeast. Our data indicate that, in addition to amino acid composition, specific sequence motifs control reversible and heritable assemblies of Sup35.
    Keywords:  IDRs; Saccharomyces cerevisiae; Sup35; [PSI+]; amyloid; osmotic stress; phase separation; prion
    DOI:  https://doi.org/10.3390/ijms27177516
  41. MedComm (2020). 2026 Sep;7(9): e70966
    Heat Shock Proteins in Cancer: Mechanisms and Therapeutic Targeting.
    Sheng Ma, Chen-Qian Liu, Si-Yang Ma, Shao-Gang Wang, Qi-Dong Xia, Meng-Yao Xu.
      Heat shock proteins (HSPs) are molecular chaperones that couple proteostasis to cancer metabolic reprogramming under oncogenic and microenvironmental stress. This Review integrates structural, biochemical, preclinical, and clinical evidence on HSP90, HSP70, HSP60, HSP40, HSP110, and small HSPs. We explain how ATPase cycles, chaperonin cages, co-chaperone networks, and organelle-specific localization stabilize metabolic enzymes, glucose transporters, hypoxia-responsive factors, and electron-transport-chain components, thereby coordinating glycolysis, mitochondrial bioenergetics, redox homeostasis, lipid metabolism, and metabolic plasticity. These mechanisms enable tumor survival and therapy resistance but also create context-dependent vulnerabilities. We critically evaluate pan-HSP and isoform-selective inhibitors, disruption of chaperone-client or co-chaperone interfaces, HSP-directed immunotherapies, and biomarker-guided combinations with metabolic or immune therapies. Clinical translation remains limited by systemic toxicity, compensatory heat-shock responses, tumor-type heterogeneity, and the absence of validated predictive biomarkers. We also assess circulating HSPs, cryo-EM analysis of chaperone complexes, and AI-assisted ligand design as routes for biomarker development and selective drug discovery. By linking chaperone architecture and client specificity to metabolic outputs and cancer phenotypes, this Review establishes a framework for differentiating actionable HSP dependencies from observational associations. It further defines priorities for patient stratification and precision oncology, supporting the development of selective and tractable strategies that target proteostasis-metabolism coupling.
    Keywords:  heat shock proteins; metabolic reprogramming; molecular chaperones; precision oncology; targeted therapy; therapy resistance
    DOI:  https://doi.org/10.1002/mco2.70966
  42. Bioact Mater. 2027 Feb;68 42-66
    From RNA design to delivery: Computational strategies for functional RNA therapeutics.
    Yiming Wang, Shengxin Tong, Xin Wang, Xiaowen Jin, Duoduo Tan, Yuan Lu.
      RNA therapeutics provide a revolutionary means of treating a variety of diseases by precisely regulating gene expression and protein synthesis, with great medical significance. However, there are three key challenges to its clinical application: the inherent instability of RNA, the need for controlled regulation of RNA function, and the lack of an efficient delivery system. Computational strategies provide complementary tools for analyzing and optimizing RNA sequence, structure, function, and delivery, accelerating the rational design of RNAs and the optimization of delivery systems. This review systematically introduces two core advances in the field of RNA therapy: (1) the design and optimization of RNAs based on predictive modeling and algorithmic screening; (2) the intelligent transformation of the delivery system through data-driven methods. Based on these developments, we discuss three future directions for computational RNA molecular design across the dimensions of design algorithms, design mechanisms, and design architectures. This review not only summarizes computational approaches developed to address key challenges in RNA therapeutics, but also highlights opportunities for integrated RNA-delivery co-design. These advances may provide useful insights for the development of next-generation precision therapeutics and their future clinical translation.
    Keywords:  Computational design; Delivery systems; Functional RNA; RNA therapeutics
    DOI:  https://doi.org/10.1016/j.bioactmat.2026.08.045
  43. Cells. 2026 Aug 27. pii: 1546. [Epub ahead of print]15(17):
    Experimental and Computational Approaches to Identify RNA-Protein Interactions.
    Brigette Romero, Jadira Aurora Fuentes Bautista, Victoria Beringer, Maryia Hrynashka, Vijay Parashar, Mona Batish.
      RNA-binding proteins (RBPs) are essential regulators of RNA metabolism and gene expression, influencing processes such as splicing, stability, localization, and translation. Despite their critical roles in health and disease, including cancer, identifying RNA-protein interactions remains challenging due to technical limitations and biases of existing methods. Here we review and compare experimental techniques-including in vitro affinity purification, in vivo crosslinking, and proximity labeling-and computational prediction tools for RBP identification. We assess their strengths, limitations, and applicability across biological contexts, emphasizing the benefits of integrating experimental and computational strategies. Our analysis provides practical guidelines for selecting appropriate methodologies tailored to different cell types and research goals. These insights aim to facilitate more accurate mapping of RNA-protein interactomes, thereby advancing understanding of RBP functions and supporting the development of novel therapeutic interventions targeting RNA-protein complexes.
    Keywords:  RBP identification; RNA-binding proteins; RNA-centric and protein-centric approaches; RNA–protein interactions; computational prediction methods; crosslinking; experimental identification methods; proximity labeling
    DOI:  https://doi.org/10.3390/cells15171546
  44. J Integr Plant Biol. 2026 Sep 16.
    An OsSK12/13-OsERF60-OsHsfA2c module regulates heat stress tolerance in rice.
    Juan Gao, Zi-Wei Yao, Zhi-Ping Deng, Jing-Jing Wang, Dong-Jie Zhu, Dai-Xi Yue, Hai-Ping Lu, Jian-Xiang Liu.
      Heat stress severely impairs plant growth and limits crop productivity. GSK3-like family proteins regulate diverse cellular processes, including plant responses to abiotic and biotic stresses. Nevertheless, their specific functions in heat stress responses remain poorly characterized. Here, we demonstrate that the expression of OsSK13 and the protein abundance of OsSK12/13 increase under heat stress in rice. Mutation in both OsSK12/13 compromises thermotolerance at both vegetative and reproductive stages, whereas overexpression of OsSK13 enhances seedling thermotolerance. We further identify that OsSK12/13 physically interact with and phosphorylate the APETALA2/ETHYLENE RESPONSIVE FACTOR (AP2/ERF) transcription factor OsERF60, and phosphorylation by OsSK12/13 enhances the stability of OsERF60. Consistent with its role in this regulatory module, OsERF60 loss-of-function mutants exhibit enhanced thermosensitivity at vegetative and reproductive stages. Expression profiling reveals that induction of heat stress-responsive genes, including OsHsfA2c, is reduced in both the OsSK12/13 double mutant and the OsERF60 mutant. OsERF60 directly binds to the OsHsfA2c promoter and activates its expression. Collectively, our findings uncover the OsSK12/13-OsERF60-OsHsfA2c regulatory module as a key component of the heat stress response in rice and provide mechanistic insights into thermotolerance in plants.
    Keywords:  GSK3‐like family protein; OsERF60; OsSK12; OsSK13; heat stress; phosphorylation; rice; thermotolerance
    DOI:  https://doi.org/10.1111/jipb.70397
  45. Mol Cell Proteomics. 2026 Sep 15. pii: S1535-9476(26)00157-X. [Epub ahead of print] 101661
    Protein Arginine Methylation of the Translation Initiation Factor eIF1A Increases Usage of a Near-cognate Start Codon.
    Rebecca Wegman, Michael Langberg, Haiteng Deng, Yuling Chen, Richoo B Davis, Xiaozhuo Liu, Minkui Luo, Michael C Yu, Sarah E Walker.
      Protein arginine methylation has emerged as a key post-translational modification responsible for many facets of eukaryotic gene expression. To better understand the extent of this modification in cellular pathways, we carried out bioorthogonal methylation profiling in Saccharomyces cerevisiae to comprehensively identify the in vivo substrates of the major yeast protein arginine methyltransferase Hmt1. Gene ontology analysis of candidate substrates revealed an enrichment of proteins involved in the process of translation. We verified one such factor, eIF1A, by in vitro methylation. Three sites on eIF1A were found to be responsible for its methylation: R13, R14, and R62, with varied capacity by which each site contributed to the overall methylation capacity in vitro. To determine the role of methylation in eIF1A function, we used a battery of arginine-to-alanine substitution mutants to evaluate translation fidelity in these mutants. Our data show that substitution mutants at R13 and R14 in the N-terminal tail improved the fidelity of start codon recognition in an initiation fidelity assay. Overall, our data suggest that Hmt1-mediated methylation of eIF1A fine-tunes the fidelity of start codon recognition for proper translation initiation.
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101661
  46. Microbiol Mol Biol Rev. 2026 Sep 15. e0009926
    Chemo-selective proteomics in microbial systems.
    Grace Z Wang, Chelsey M VanDrisse.
      SUMMARYOver the past two decades, the field of bioorthogonal chemistry has transitioned from emerging to an established cornerstone of scientific inquiry. In parallel, advances in microbial and host-microbe research have highlighted the need for functional approaches that extend beyond genomic and transcriptomic analyses to directly interrogate protein-level activity. Despite this need, proteomic strategies capable of resolving dynamic, heterogeneous, and low-abundance protein populations remain underdeveloped in microbial systems. This review highlights the convergence of chemo-selective proteomic technologies with microbial biology, focusing on bioorthogonal non-canonical amino acid tagging (BONCAT), activity- or affinity-based protein profiling, and bioorthogonal post-translational modifications, and comments on possibilities for novel applications for the use of click chemistry-based tools in the functional interrogation of microbial systems. Together, these strategies enable spatiotemporal resolution of protein synthesis, selective profiling of microbial subpopulations, and direct characterization of protein activity and regulation in complex biological contexts, including single-species cultures, host-associated environments, and polymicrobial communities. Continued development and utilization of these technologies will enable deeper mechanistic insight into how microbial systems function and respond to environmental and host-derived cues.
    Keywords:  bioorthogonal chemistry; chemo-selective proteomics; chemoproteomics; click chemistry; enzymology; mass spectrometry; post-translational modifications (PTMs); protein synthesis; protein–protein interactions
    DOI:  https://doi.org/10.1128/mmbr.00099-26
  47. Clin Sci (Lond). 2026 Sep 15. pii: CS20261973. [Epub ahead of print]
    circNfix attenuates acute kidney injury by driving m6A-dependent degradation of YTHDF2 to stabilize DAPK2 mRNA.
    Tongtong Ma, Ziqi Zhang, Yilin Yang, Chaopeng Chen, Zhiyi Li, Huasheng Luo, Yanmei Yu, He Huang, Zhongqing Chen, Peng Wang.
      Although circular RNAs (circRNAs) have been implicated in acute kidney injury (AKI), their functional mechanisms beyond acting as miRNA sponges remain poorly understood, and the role of N6-methyladenosine (m6A) modification in circRNA-mediated regulation in AKI is yet to be explored. Here, we identify a novel mechanism by which the m6A-modified circRNA circNfix contributes to the regulation of septic AKI (SAKI). In tubular epithelial cells (TECs), downregulation of RBM47 reduces circNfix expression during SAKI. m6A-modified circNfix scaffolds the E3 ligase HECTD1 to induce K48-linked polyubiquitination and proteasomal degradation of the m6A reader YTHDF2. This stabilizes DAPK2 mRNA, a key target of YTHDF2, inhibiting NF-κB activation, thereby reducing TEC apoptosis and inflammation. In mouse models of SAKI and ischemia-reperfusion injury-AKI, AAV-mediated circNfix delivery lowered YTHDF2, suppressed inflammation, improved renal function, and attenuated damage. In septic AKI patients, circNfix levels in plasma and urine were significantly decreased, negatively correlated with serum creatinine. Urinary and plasma circNfix showed diagnostic potential. Our study reveals a mechanism where an m6A-modified circRNA contributes to AKI progression by degrading its reader protein, suggesting that circNfix may represent a potential therapeutic target and non-invasive biomarker.
    Keywords:  N6-methyladenosine; NF-κB; acute kidney injury; circular RNA; tubular epithelial cell
    DOI:  https://doi.org/10.1042/CS20261973
  48. Mar Biotechnol (NY). 2026 Sep 16. pii: 157. [Epub ahead of print]28(5):
    The Effects of Disrupting Ca2+ Homeostasis on the ERs and Lipid Metabolism in the Hepatopancreas of Penaeus vannamei Exposed to Ammonia Stress.
    Wenheng Li, Changjian Li, Meng Cong, Fang Wang, Hongwei Shan.
      Ca2+ homeostasis regulates endoplasmic reticulum (ER) stress and lipid metabolism and is involved in the stress response in mammals. However, how these regulatory pathways respond in aquatic animals exposed to stressful environmental conditions remains unclear. In this study, we used siRNA to inhibit the expression levels of Bip, SERCA, IP3R, and MCU, which are involved in regulating Ca2+ homeostasis in the hepatopancreas of Penaeus vannamei. An ammonia stress experiment was subsequently conducted (stress concentration of 11.3 mg/L) to measure parameters associated with ER stress, Ca2+ homeostasis, and lipid metabolism. This study was performed to verify the roles of Ca2+ homeostasis in regulating ER stress and lipid metabolism in P. vannamei subjected to ammonia stress. Interfering with Bip gene expression limited the unfolded protein reaction (UPR), reduced Ca2+ transport into the ER, and promoted Ca2+ efflux. These findings indicate that Bip plays a critical role in the regulation of ER stress and Ca2+ homeostasis. Interfering with SERCA gene expression exacerbated ER stress responses and promoted the UPR. This interference also reduced ER Ca2+ leakage through IP3R and aggravated the cellular energy deficiency state, indicating that SERCA is crucial for maintaining ER Ca2+ levels and managing energy balance. Reduced IP3R gene expression inhibited ER stress responses by decreasing Ca2+ efflux from the ER. This reduction in Ca2+ transport into the ER and mitochondria resulted in cellular energy deficiency and modulated lipid metabolism, highlighting the role of IP3R in Ca2+ signaling and metabolic regulation. Interfering with MCU gene expression alleviated ROS-induced ERs, led to ER Ca2+ overload, and resulted in cellular energy deficiency while enhancing lipid metabolism. These findings indicate that MCU is vital for regulating mitochondrial Ca2+ uptake and cellular energy metabolism under stress conditions. These results suggest that reducing ER Ca²⁺ efflux and maintaining ER Ca²⁺ homeostasis represent candidate molecular targets whose contributions to ammonia tolerance in shrimp are worth investigating in future studies.
    Keywords:   Penaeus vannamei ; Ammonia stress; Ca2+ homeostasis; ERs; siRNA
    DOI:  https://doi.org/10.1007/s10126-026-10709-z
  49. Protein Sci. 2026 10;35(10): e70780
    Function within disorder: Small heat shock proteins use different functional regions to chaperone tau aggregation.
    Mia Cervantes, Maria K Janowska, Lisa M Tuttle, Miklos Guttman, Abhinav Nath, Rachel E Klevit.
      In numerous neurodegenerative diseases known collectively as tauopathies, the microtubule-associated protein tau forms fibrillar aggregates that are hallmarks of disease pathology. Tauopathies represent a substantial fraction of diseases associated with protein misfolding. Cellular chaperones known as small heat shock proteins (sHSPs) play a critical role in maintaining protein homeostasis by delaying the onset of protein aggregation. Two sHSPs, HSPB1 (Hsp27) and HSPB5 (αB-crystallin), are constitutively expressed in the brain and neurons. Here, we show that HSPB1 and HSPB5 delay tau aggregation in vitro through distinct mechanisms dictated by their disordered N-terminal regions (NTRs). HSPB1 inhibits tau aggregation under normal cellular conditions, whereas HSPB5 displays activity toward tau when activated by stress conditions such as pH acidosis. Using chimeric HSPB1/HSPB5 constructs in which small NTR subregions are swapped, we identify functional regions within the NTRs that modulate chaperone function for tau. The functional regions contain known sites of phosphorylation, suggesting that they are also control points that respond to cellular stress conditions. Our findings support an emerging model in which specific functional motifs within disordered regions of sHSPs govern activity and client engagement under normal and stress conditions.
    Keywords:  HSPB1; HSPB5; Hsp27; chaperone; intrinsic disorder; protein aggregation; small heat shock proteins; tau aggregation; αB‐crystallin
    DOI:  https://doi.org/10.1002/pro.70780
  50. Curr Top Dev Biol. 2026 ;pii: S0070-2153(26)00077-3. [Epub ahead of print]170 345-372
    Transcription elongation mechanisms that control gene expression in erythropoiesis.
    Kaustav Mukherjee, James J Bieker.
      The regulation of RNA transcript abundance relies on the control of two key early steps in gene expression: transcription initiation and productive elongation. Although DNA-directed RNA polymerase provides the intrinsic catalytic activity required for RNA synthesis, its ability to effectively produce a transcript relies on accurate recruitment to specific DNA sites to initiate RNA polymerization, followed by release from promoter-proximal pausing into a productive elongation machine. These steps are governed by accessory factors that not only facilitate the assembly of a functional pre-initiation complex but also exert both negative and positive control over polymerase pause/elongation status. We describe experiments that have elucidated these mechanisms in the context of erythropoiesis.
    Keywords:  Erythropoiesis; Pausing/elongation; RNA polymerase; Transcriptional burst; mRNA transcription
    DOI:  https://doi.org/10.1016/bs.ctdb.2026.06.004
  51. G3 (Bethesda). 2026 Sep 16. pii: jkag245. [Epub ahead of print]
    Analysis of proteasome stress in different cell types defines a conserved transcriptional response signature and its modulation with aging.
    Mamta Rai, Yong-Dong Wang, Anna Stephan, Anjana Nityanandam, Fabio Demontis.
      The proteasome is essential for proteostasis. Transcriptional induction of proteasomal components occurs when the proteasome is inhibited, but an overview of the transcriptional responses caused by proteasome perturbation is missing. Here, we profiled transcriptional changes caused by chemical and genetic proteasome inhibition and defined time-dose responses in cells and organoids. Induction of proteasome components varied by cell type and inhibition mode, whereas other responses were consistent, including upregulation of chaperones and secreted factors, and repression of cell cycle regulators. A proteasome stress response signature was defined based on the genes consistently modulated across systems, and applying this signature to aging datasets revealed activation of this stress response in some tissues, including skeletal muscle. Moreover, secreted factors within the signature showed similar age-related changes in human plasma, suggesting systemic activation of this stress response with aging. Together, these findings define a transcriptional signature for monitoring proteasome stress during aging and age-related diseases.
    Keywords:  aging; organoids; proteasome; proteostasis; stress response; stress signature
    DOI:  https://doi.org/10.1093/g3journal/jkag245
  52. Protein Sci. 2026 10;35(10): e70774
    EvoMut: A computational framework for engineering oxidative stability in proteins.
    Seyed Shahriar Arab, Chenlin Hsieh, Nathan E Lewis.
      Amino acid oxidation is a major cause of protein instability and loss of function in therapeutic and industrial settings. Although methionine, cysteine, tryptophan, tyrosine, histidine, lysine, and arginine residues are widely recognized as oxidation-prone, only a subset of such residues is dominant functional hotspots, and not all are suitable targets for mutation. Identifying these vulnerable, yet engineerable, sites remains a major challenge. Here, we present EvoMut, a residue-level analytical framework for evaluating both oxidative vulnerability and mutation feasibility. EvoMut estimates oxidation risk by integrating structural features, local functional context, intrinsic chemical susceptibility, and evolutionary conservation. A central feature of the framework is the explicit separation of oxidation risk from mutation feasibility. Specifically, candidate substitutions are evaluated only after high-risk residues are identified and ranked by evolutionary substitution patterns. Application of EvoMut to multiple proteins, and evaluation with experimental data, showed that oxidation-prone residues differ markedly in their engineering potential. EvoMut distinguishes residues that are both oxidation-sensitive and evolutionarily permissive from those that are chemically vulnerable but functionally constrained. By providing residue-level mechanistic insight, EvoMut offers a practical framework for the rational design of oxidation-resistant proteins. EvoMut is freely available as a web server at https://proteus.cmm.uga.edu/evomut.
    Keywords:  evolutionary conservation; oxidative hotspot prediction; oxidative stability engineering; protein engineering; protein oxidation; structural bioinformatics
    DOI:  https://doi.org/10.1002/pro.70774
  53. Int J Mol Sci. 2026 Aug 25. pii: 7606. [Epub ahead of print]27(17):
    LRRK2: Molecular Mechanisms in Parkinson's Disease.
    Oscar Arias-Carrión, Magdalena Guerra-Crespo, Daniel Ortuño-Sahagún, Emmanuel Ortega-Robles.
      Leucine-rich repeat kinase 2 (LRRK2) has emerged as a central molecular node linking genetic risk, membrane trafficking, lysosomal homeostasis, and immune signalling in Parkinson's disease (PD). Rather than functioning as a conventional protein kinase, LRRK2 operates as a conformationally regulated, Rab-directed signalling machine whose activity is governed by long-range interdomain communication, membrane recruitment, and cooperative interactions with small GTPases. Converging advances in cryo-electron microscopy, quantitative phosphoproteomics, and human genetics indicate that pathogenic mutations, lysosomal stress, and pharmacological inhibitors do not simply alter catalytic output, but reshape the conformational landscape of LRRK2, biasing it toward distinct structural states with divergent cellular consequences. A defining feature of this system is the selective phosphorylation of Rab GTPases at low stoichiometry-most prominently Rab8 and Rab10-yet with disproportionate functional impact on vesicle trafficking, ciliogenesis, autophagy, and organelle positioning. The identification of Rab-directed phosphatases, particularly PPM1H, further establishes that LRRK2 signalling is governed by a dynamically balanced kinase-phosphatase circuit operating in space and time. These observations, together with emerging evidence linking LRRK2 activation to lysosomal damage and immune pathways, support a unifying hypothesis: PD-associated LRRK2 dysfunction arises from maladaptive stabilization of specific conformational and spatial states within a membrane-responsive signalling network, leading to persistent misregulation of Rab-dependent trafficking and organelle homeostasis, rather than from kinase hyperactivity alone. In this review, we integrate structural, biochemical, and cellular evidence to advance this framework and discuss its implications for disease mechanisms and therapy. We highlight key unresolved challenges-including conformation-selective drug targeting, spatial control of Rab phosphorylation, and context-dependent immune-neuronal crosstalk-and propose that restoring physiological regulation of LRRK2, rather than simply inhibiting its activity, will be essential for achieving mechanism-based disease modification in Parkinson's disease.
    Keywords:  LRRK2; Parkinson’s disease; Rab GTPases; conformational regulation; cryo–electron microscopy; lysosomal stress
    DOI:  https://doi.org/10.3390/ijms27177606
  54. Oncol Rep. 2026 Nov;pii: 186. [Epub ahead of print]56(5):
    [Expression of Concern] RIP kinase‑mediated ROS production triggers XAF1 expression through activation of TAp73 in casticin‑treated bladder cancer cells.
    Yoon Hee Chung, Daejin Kim.
      Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the JNK western blotting data shown in Fig. 2E on p. 1138 were strikingly similar to the JNK western blotting data shown in Fig. 4D on p. 1139, even though the experimental conditions reported for these figure parts were apparently different. The authors have been contacted by the Editorial Office to offer an explanation for the apparent re‑use of the same data in this paper, and the authors have replied to explain that these studies were performed several years ago, that they no longer have access to the original data, and moreover, that they are not in a position to repeat any of these experiments. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem associated with the abovementioned data. [Oncology Reports 36: 1135‑1142, 2016; DOI: 10.3892/or.2016.4895].
    Keywords:  RIP kinase; XIAP associated factor 1; bladder cancer; casticin; transcriptionally active p73
    DOI:  https://doi.org/10.3892/or.2026.9192
  55. ACS Chem Biol. 2026 Sep 14.
    Elucidating the Requirements for microRNA-Mediated Upregulation Enables Reengineering of Upregulatory Sites.
    Helia Dehghan Harati, Thusini Uggalla Arachchige, Xinghai Liu, Lara K Mahal.
      The post-transcriptional regulation of protein expression by miRNA has given rise to new technologies for therapeutic interventions and synthetic biology. To date, these technologies assume that miRNAs are repressors of protein expression; however, emerging evidence has shown that miRNA regulation of proteins is bidirectional. Although it is now clear that upregulation by miRNAs is a common event, the molecular requirements remain poorly characterized. To address this gap, we utilized the miRFluR assay, a genetically encoded dual-fluorescence reporter assay previously developed in our laboratory, to systematically explore upregulation. Using upregulation of the enzyme B3GLCT by miR-891b as a model system, we find that upregulation requires both specific sequence elements and RNA secondary structure. Mutagenesis and truncation analyses revealed that the effect is context-dependent and influenced by the local UTR structure. We also find that sites can be reengineered to be triggered by alternate miRNA, opening the door to synthetic biology manipulations. Our study provides a new perspective on upregulation by miRNA and sets the stage for further exploration of the bidirectional nature of miRNA action.
    DOI:  https://doi.org/10.1021/acschembio.6c00503
  56. Animals (Basel). 2026 Aug 31. pii: 2700. [Epub ahead of print]16(17):
    Advances in Poultry RNA-Omics Research: Technologies, RNA Information Layers, and Applications in Complex Traits.
    Wenbin Dao, Simeng Zhang, Tao Zhang, Xinyang Fan, Yongwang Miao.
      RNA-omics technologies have expanded poultry transcriptome research beyond tissue-level gene abundance. They now resolve intact transcripts, RNA chemical modifications, cellular origins, and spatial locations. This review centers on a core question: what specific, previously inaccessible RNA information does each RNA-omics technology provide? Based on their primary measurement targets, we categorize these technologies into four groups: bulk transcriptome and small RNA sequencing for analyzing gene expression and regulatory RNA networks; long-read and direct RNA sequencing for resolving transcript isoforms; epitranscriptomic methods for detecting RNA modifications; and single-cell and spatial transcriptomics for identifying the cellular origins and spatial distributions of signals. Methods for resolving RNA structure, RNA-protein interactions, and translation status (e.g., structure probing, CLIP-type mapping, and ribosome profiling) remain in their infancy in poultry, leaving translation and RNA-protein regulation largely unmeasured in tissues such as the oviduct, the lipogenic liver and nucleated erythrocytes. For each category, we discuss its direct measurement targets and primary outputs, the additional information it provides compared to established methods, representative applications in poultry, and its inherent limitations. Building on this framework, we discuss how to select and combine technologies based on specific research questions and summarize their applications in studies of production performance and product quality, reproduction, and health and resilience. Different technologies measure distinct types of RNA features and are not simply interchangeable. Future research must place greater emphasis on matching technologies to scientific questions, integrating complementary data, and improving three foundations: the annotation of poultry transcripts and non-coding RNAs, standardized analytical pipelines, and functional validation systems.
    Keywords:  RNA-omics; complex traits; epitranscriptomics; long-read RNA sequencing; poultry; single-cell and spatial transcriptomics
    DOI:  https://doi.org/10.3390/ani16172700
  57. J Biol Chem. 2026 Sep 17. pii: S0021-9258(26)02445-2. [Epub ahead of print] 113573
    RNA demethylase FTO uses conserved aromatic residues to recognize the mRNA 5' cap and promote efficient m6Am demethylation.
    Brittany Shimanski, Juan F Marin, Marcin Warminski, Kasun Dilshan Abeyrathne Eluwawalage, Lucas O Calzini, Riley M McKeon, Joanna Kowalska, Jacek Jemielity, Jodi A Hadden-Perilla, Jeffrey S Mugridge.
      The RNA demethylase FTO acts as a methyl 'eraser' to remove either internal N6-methyladenosine (m6A) or 5' end N6-2'-O-dimethyladenosine (m6Am) modifications on mRNA. FTO has an intrinsic preference and significantly faster demethylation rates in vitro for m6Am modifications located at the 5' mRNA cap structure, but the structural basis for FTO's ability to discriminate m6A versus m6Am modifications has remained unknown. Here we utilize molecular dynamics simulations of FTO-RNA cap complexes to identify conserved aromatic residues on the surface of FTO involved in 5' cap recognition. Subsequent mutagenesis and enzymology experiments validate the specificity of these residues in engaging the 5' cap structure to promote m6Am demethylation. We also identify a nonpolar surface on FTO that interacts with the 2'-O-methyl group of m6Am to impact demethylation kinetics. This work provides the first structure-level insights into how FTO selectively catalyzes m6Am versus m6A demethylation on mRNA and advances our understanding of how FTO activity is regulated by diverse mechanisms to help control the epitranscriptome.
    Keywords:  RNA demethylation; RNA modification; RNA–protein interaction; enzyme catalysis; enzyme kinetics; molecular dynamics
    DOI:  https://doi.org/10.1016/j.jbc.2026.113573
  58. Nucleic Acids Res. 2026 Sep 07. pii: gkag882. [Epub ahead of print]54(17):
    Molecular basis of tRNA substrate recognition and modification by the atypical SPOUT methyltransferase Trm10.
    Suparno Nandi, Sarah E Strassler, Debayan Dey, Catherine B Whitney, Olivia B Roumaya, Aiswarya Krishnamohan, George M Harris, Lindsay R Comstock, Jane E Jackman, Graeme L Conn.
      The evolutionarily conserved methyltransferase Trm10 catalyzes N1 methylation of guanosine 9 (G9) in selected tRNAs, but the basis of specific substrate recognition and modification has remained unclear. Using an S-adenosyl-l-methionine analog, we trapped a post-catalytic state of the Trm10-tRNAGly complex for structure determination by cryogenic electron microscopy. Three distinct complexes were captured: two monomeric Trm10-tRNA complexes with distinct tRNA acceptor stem orientations ("closed" and "open"), and a minor dimeric complex with two Trm10s bound to the same tRNA. The monomeric structures identify conserved residues involved in tRNA interactions across a positively charged surface that guide G9 into the catalytic site and stabilize the flipped nucleotide. In the tRNAopen conformation, acceptor stem rotation weakens tRNA-protein contacts, consistent with a product-release state. The dimeric complex, supported by tRNA-dependent protein crosslinking and molecular dynamics (MD) simulations, positions one Trm10 on G9 similarly to the monomeric complexes, while the other contacts distal tRNA regions, suggesting a functional role in promoting functionally critical conformational transition(s). MD simulations also show how Trm10 achieves selective stabilization of G9 over A9 in the binding pocket. Overall, our findings reveal the mechanism of G9-specific tRNA methylation by Trm10 and suggest a unique mechanism of action among RNA-modifying SPOUT methyltransferases.
    DOI:  https://doi.org/10.1093/nar/gkag882
  59. Biochim Biophys Acta Gene Regul Mech. 2026 Sep 15. pii: S1874-9399(26)00050-7. [Epub ahead of print]1869(4): 195184
    Short-lived lncRNAs as candidate kinetic sensors of cellular stress.
    Hidenori Tani.
      Short-lived noncoding transcripts (SLiTs; half-life <4 h) form a kinetically distinct subclass of long noncoding RNAs (lncRNAs) whose rapid turnover is an active regulatory feature rather than a measurement artefact. This review has three objectives: to set out the kinetic basis on which a short half-life supports sensor-like behaviour; to define operational criteria that separate a candidate kinetic sensor from a merely stress-responsive unstable transcript; and to assess the evidence for SLiT involvement across the xenobiotic, oxidative, and proteotoxic stress axes. The evidence differs sharply in weight between axes. Direct mechanistic data exist only for chemical stress in HepG2 cells, where SLiT accumulation arises from transcript stabilisation rather than increased transcription, with impairment of the nuclear exosome and XRN2 as the leading candidate mechanism. The oxidative and proteotoxic axes remain hypothesis-generating. Cross-cell-type and cross-species validation is absent, and the limitations this imposes are stated explicitly.
    Keywords:  BRIC-seq; Long noncoding RNA; RNA exosome; RNA half-life; Short-lived transcript (SLiT); Stress response
    DOI:  https://doi.org/10.1016/j.bbagrm.2026.195184
  60. Front Immunol. 2026 ;17 1960492
    Organelle-centered ISG15 biology: distinguishing covalent ISGylation from interferon-associated responses.
    Zhuoer Li, Chunli Wang, Jinrong Zhang, Zhiqiang Guo.
      ISGylation is an interferon-inducible ubiquitin-like post-translational modification mediated by the interferon-stimulated gene 15 conjugation system. Initially characterized as an antiviral effector pathway, ISGylation is now increasingly recognized as a regulator of organelle homeostasis and cellular stress responses. This review summarizes emerging evidence linking ISG15-related mechanisms and covalent ISGylation to major organelle systems, including mitochondria, the endoplasmic reticulum-Golgi axis, endolysosomal compartments, ribosome-associated translation, and lipid droplets. We distinguish covalent ISGylation from free ISG15 signaling and ubiquitin specific protease 18-mediated interferon regulation, and further classify existing findings into evidence-based levels ranging from substrate-validated modification to correlative interferon signatures. At the mitochondrial level, direct and pathway-level evidence implicates ISG15 biology in DRP1-mediated fission, MFN1/2-associated mitophagy, oxidative metabolism, and redox regulation; direct effects of MFN1/2 ISGylation on mitochondrial fusion remain unproven. Along the ER-Golgi axis, ISG15-related pathways intersect with unfolded protein response signaling, endoplasmic reticulum-associated degradation, and stimulator of interferon genes-mediated innate immune activation. In the endolysosomal system, ISGylation and ISG15-associated pathways modulate autophagic flux, multivesicular body fate, and exosome secretion in a context-dependent manner. Ribosome-associated co-translational ISGylation links nascent protein surveillance with antiviral defense, whereas lipid droplet-associated ISG15/ISGylation pathways are linked to lipid metabolism and immune signaling. Current evidence supports an organelle-centered view of ISG15 biology but indicates that validated covalent mechanisms remain confined to selected substrates and contexts. Clinical translation will require organelle-resolved ISGylome mapping, substrate-level validation, and standardized biomarker assays before context-selective targeting can be considered.
    Keywords:  ISG15; ISGylation; autophagy; biomarkers; endoplasmic reticulum stress; mitochondrial dynamics; organelle homeostasis
    DOI:  https://doi.org/10.3389/fimmu.2026.1960492
  61. Int J Mol Sci. 2026 Sep 02. pii: 7859. [Epub ahead of print]27(17):
    Damage-Associated Molecular Patterns in Mesothelioma: Drivers of Inflammation and Therapeutic Targets.
    Annamaria Molinario, Francesca Caprioglio, Angela A Rilievo, Marco E Bianchi, Rosanna Mezzapelle.
      Mesothelioma is a rare and aggressive malignancy arising from mesothelial cells. Despite recent advances in systemic therapies, overall survival remains limited, underscoring the need for a deeper mechanistic understanding of disease pathogenesis and novel therapeutic strategies. In mesothelioma, chronic tissue injury induced by asbestos fibers leads to sustained activation of innate immune pathways and chronic inflammation that actively promote tumorigenesis. The release of Damage-Associated Molecular Patterns (DAMPs)-endogenous molecules that signal cellular stress and damage-contributes to establishing a self-sustaining inflammatory circuit within the pleural microenvironment that promotes tumor initiation and progression and immune evasion. Among DAMPs, High-Mobility Group Box 1 (HMGB1) has emerged as a key regulator of mesothelioma pathogenesis. Several studies demonstrated that mesothelial cells actively secrete HMGB1 in response to asbestos exposure, driving macrophage recruitment, cytokine production, and chronic inflammation. Beyond HMGB1, additional DAMPs-including IL-33, extracellular ATP, cell-free nucleic acids, heat shock proteins, and calreticulin-contribute to inflammasome activation, stromal remodeling, and immune dysregulation. Recent evidence suggests that DAMP signaling in mesothelioma is dysregulated, resulting in chronic inflammation coupled with ineffective antitumor immunity. This review provides a comprehensive synthesis of DAMP biology in mesothelioma, highlighting the emerging therapeutic opportunities targeting DAMP-associated pathways.
    Keywords:  damage associated molecular patterns; inflammation; mesothelioma
    DOI:  https://doi.org/10.3390/ijms27177859
  62. Biochem Pharmacol. 2026 Sep 16. pii: S0006-2952(26)00823-3. [Epub ahead of print] 118481
    RNF5: an emerging therapeutic target for modulating immunity and metabolism.
    Ruobing He, Jiao Wang, Mengjia Lin, Yuxin Su, Zhuoran Li, Wei Dong, DanFeng Zhang, Xiaowen Yu.
      Ring finger protein 5 (RNF5), a membrane-associated RING-type E3 ubiquitin ligase, serves as a critical regulator of cellular homeostasis by controlling protein stability, metabolic adaptation, and immune signaling. This review provides a comprehensive overview of the multifaceted functions of RNF5, with particular emphasis on its context-dependent roles in cancer progression, antiviral immunity, and non-neoplastic diseases. In cancer, RNF5 exhibits highly context-dependent and sometimes paradoxical functions that are influenced by cellular environments, disease stages, and substrate availability. RNF5 regulates tumor-associated metabolic reprogramming by targeting glutamine transporters and key regulators of lipid metabolism. Moreover, through interactions with autophagy-related proteins and Ephrin receptors, RNF5 modulates tumor growth, therapeutic resistance, and antitumor immune responses. These findings highlight RNF5 as a complex regulator of tumor biology with both oncogenic and tumor-suppressive potential. During viral infections, RNF5 demonstrates dual regulatory activities in host-pathogen interactions. On one hand, RNF5 can suppress antiviral innate immune signaling by promoting the ubiquitination and degradation of key immune adaptors, including STING and MAVS. On the other hand, RNF5 may restrict viral replication by directly targeting viral components, such as the SARS-CoV-2 envelope protein and foot-and-mouth disease virus VP1, for ubiquitination and degradation. Thus, RNF5 functions as a versatile modulator of antiviral defense, with effects determined by the specific viral context and host signaling landscape. Beyond cancer and viral infection, emerging evidence implicates RNF5 in a variety of non-neoplastic disorders. RNF5 contributes to protein quality control in neurodegenerative diseases by facilitating the clearance of pathological tau through the ERAD pathway. In addition, genetic inhibition of RNF5 ameliorates intestinal pathological phenotypes in a mouse model of cystic fibrosis, while RNF5 has also been associated with hepatic and cardiovascular injury responses through regulation of cellular stress pathways. From a therapeutic perspective, RNF5-targeting strategies, including small-molecule inhibitors and pathway modulators, have emerged as potential approaches for manipulating RNF5-associated biological processes. However, substantial challenges remain, including achieving target specificity, understanding the context-dependent consequences of RNF5 modulation, minimizing potential disruptions to proteostasis and innate immune regulation, and developing clinically feasible therapeutic interventions. This review summarizes the complex regulatory network governed by RNF5 and discusses future opportunities and challenges in translating mechanistic insights into therapeutic applications while carefully considering potential risks associated with RNF5 targeting.
    Keywords:  Antiviral immunity; Cancer metabolism; Metabolic disorders; RNF5; Therapeutic targeting; Ubiquitination
    DOI:  https://doi.org/10.1016/j.bcp.2026.118481
  63. PLoS Pathog. 2026 09;22(9): e1014571
    Dual regulation of the receptor-like kinase BIR1 involves site-directed transcript cleavage and 5'-leader-mediated translational control.
    Irene Guzmán-Benito, Carmen Robinson, Livia Donaire, Lourdes Fernández-Calvino, José Manuel Franco-Zorrilla, Ruixia Niu, Guoyong Xu, Catharina Merchante, César Llave.
      In Arabidopsis, BRASSINOSTEROID INSENSITIVE1-ASSOCIATED RECEPTOR KINASE 1 (BAK1)-INTERACTING RECEPTOR-LIKE KINASE 1 (BIR1) is a negative regulator of plant immunity and cell death. BIR1 was earlier described as a target of epigenetic and post-transcriptional degradation. During virus infections, degradome analysis of BIR1 transcripts mapped predominant mRNA cleavage sites at the 5'-untranslated leader region (site A) and the protein-coding sequence (sites B and C). Here, we identified another virus-associated cleavage site (D) within the BIR1 coding region and investigated the contribution of site-directed mRNA cleavage to BIR1 regulation. Mutations at B, C, and D sites enhanced mRNA stability by impairing transcript cleavage, resulting in increased BIR1 mRNA and protein accumulation. This regulation is disrupted in RNA silencing mutants, supporting a model of cis-directed small interfering RNA (siRNA)-mediated degradation. We next demonstrate that virus infection reduces BIR1 translation in Arabidopsis. Furthermore, our data reveal a repressive role for the 5'-leader in regulating BIR1 translation, potentially mediated by upstream open reading frames (uORFs) and a virus-responsive long non-coding RNA (lncRNA) derived from the natural antisense At4g39838 locus. Together, these findings reveal a multilayered regulatory mechanism that integrates sRNA-mediated cleavage with translational control, with broader implications for the fine-tuning of stress-responsive gene expression during infection.
    DOI:  https://doi.org/10.1371/journal.ppat.1014571
  64. Free Radic Biol Med. 2026 Sep 15. pii: S0891-5849(26)01161-5. [Epub ahead of print]256 516-530
    Nicotine modulates α7nAChR associated ceramide-mitochondrial stress responses in Parkinsonian models.
    Gaoge Wang, Zhen Ni, Jingzheng Zhang, Qian Li, Yunfu Tan, Hao Yu, Enliang Hong, Chunmei Guang, Shu Wang, Huan Chen, Hongwei Hou.
      Parkinson's disease (PD) is characterized by progressive dopaminergic degeneration accompanied by mitochondrial dysfunction and oxidative stress, yet the metabolic mechanisms underlying these pathological changes remain incompletely understood. Here, we investigated whether nicotine preserves dopaminergic integrity by modulating ceramide homeostasis through α7 nicotinic acetylcholine receptor (α7nAChR) signalling. In an MPTP mouse model, nicotine improved motor and exploratory deficits, preserved striatal tyrosine hydroxyl positive fibres, and selectively reversed ceramide accumulation in the striatum and plasma. Transcriptional analysis further showed that nicotine suppressed the induction of ceramide biosynthetic genes, suggesting regulation of sphingolipid remodelling in vivo. In MPP + challenged SH-SY5Y cells, nicotine restored cell viability, mitochondrial membrane potential, respiratory function, and mitochondrial morphology while reducing reactive oxygen species (ROS) production and apoptosis. Time-resolved analyses revealed that nicotine modulated an evolving stress response, in which early oxidative stress preceded detectable ceramide accumulation, while later ceramide dysregulation was associated with sustained mitochondrial vulnerability. Targeted lipidomics confirmed that nicotine directly restrained ceramide accumulation in stressed neuronal cells. Genetic (siSPTLC1 or siCHRNA7), pharmacological (Myriocin or MLA), and exogenous ceramide supplementation studies further supported a model in which nicotine limits this ceramide associated mitochondrial stress response through α7nAChR associated metabolic regulation. Mechanistically, nicotine restored AKT signalling and the BCL2 to BAX balance while suppressing cleaved caspase-3. Together, these findings identify ceramide dysregulation as a functionally relevant component of Parkinsonian mitochondrial stress responses and support an α7nAChR associated ceramide regulatory mechanism through which nicotine limits neuronal vulnerability.
    Keywords:  Ceramide; Mitochondrial dysfunction; Nicotine; Parkinson's disease; ROS; α7nAChR
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.09.010
  65. Protein Pept Lett. 2026 Aug 19. pii: S0929-8665(26)00006-8. [Epub ahead of print]34(2): 43-63
    Heat shock proteins as modulators of cardiovascular health and disease: From cellular stress to clinical targets.
    Niloofar Naderi, Azam Bolhassani, Fatemeh Pirani.
      Cardiovascular disease (CVD) is a result of complex pathophysiological processes affecting the heart and blood vessels. Heat shock proteins (HSPs) are evolutionarily conserved molecular chaperones that play key roles in maintaining protein homeostasis and cell survival under various stress conditions. Studies have shown the role of HSPs in diseases, including autoimmune disorders, liver, pancreatic, cancer, diabetes, and kidney disorders. Important findings regarding the role of HSPs in cardiovascular diseases include atherosclerosis, ischemic heart disease, atrial fibrillation, cardiomyopathy, heart failure, deep vein thrombosis, and peripheral vascular disease. Several proteins related to HSPs have been identified in various molecular mechanisms, including autophagy, apoptosis, oxidative stress, inflammatory responses, and fibrosis in cardiac disease. This review provides a comprehensive overview of the molecular biology and classification of HSPs, including extracellular HSPs, small HSPs, and co-chaperone molecules. We explored the roles of HSPs in regulated cell death mechanisms and in modulating oxidative stress and inflammatory responses. Furthermore, we demonstrated the pathological and protective roles of specific HSPs by regulating gene expression in response to drugs and cytokines, including geldanamycin and geranylgeranylacetone (GGA), across various cardiovascular conditions, highlighting the potential for HSP-targeted therapies. Promising strategies, including small-molecule inhibitors, inducers, and gene therapies, such as Bcl-2-associated athanogene 3 (BAG3) modulation, are discussed in the context of clinical relevance and therapeutic potential. However, despite promising experimental and clinical evidence, the translational application of HSPs remains limited by their context-dependent biological functions, the lack of standardized biomarker assays, heterogeneous clinical findings, and insufficient large-scale prospective validation. This narrative review was not prospectively registered, and received no external funding. It was conducted by searching PubMed, Scopus, Google scholar and Web of Science for relevant published articles. Understanding the multifaceted roles of HSPs offers new insights into cardiovascular disease mechanisms and paves the way for novel diagnostic and therapeutic approaches.
    Keywords:  Cardiovascular disease; Drug targets; Heat shock proteins
    DOI:  https://doi.org/10.1016/j.ppl.2026.08.002
  66. Cells. 2026 Sep 04. pii: 1613. [Epub ahead of print]15(17):
    Differential Modulation of the DR5-JNK-PD-L1 Signaling Axis by TRiC/CCT Subunits CCT7 and CCT2 Shapes Tumor Immune Evasion in Lung Adenocarcinoma.
    Hsin-Wei Jen, Hsiang-Ling Ho, Teh-Ying Chou.
      While the chaperonin-containing TCP-1 (CCT) complex is essential for proteostasis, the distinct roles of individual subunits in tumor immune regulation remain unclear. Here, we identify CCT7 as a previously unrecognized regulator of immune evasion in lung adenocarcinoma (LUAD). Integrative analyses of TCGA and GEO cohorts revealed that CCT7 is markedly upregulated in LUAD and is associated with poor patient prognosis. Functional studies demonstrated that CCT7 knockdown inhibited tumor cell proliferation and migration and enhanced cisplatin-induced apoptosis, yet paradoxically impaired T-cell activation. Mechanistically, transcriptomic and biochemical analyses revealed that CCT7 depletion activated the DR5-MKK4-JNK-c-Jun signaling cascade, resulting in the transcriptional upregulation of PD-L1. Disruption of DR5 or JNK signaling effectively abrogated PD-L1 induction. In contrast, CCT2 depletion exerted the opposite effect by suppressing the DR5-JNK-c-Jun-PD-L1 signaling axis and enhancing T-cell activation. Collectively, these findings reveal unexpected functional divergence among TRiC/CCT subunits and identify the CCT7-DR5-JNK-c-Jun signaling axis as a previously unrecognized mechanism regulating PD-L1-mediated immune evasion, highlighting the potential therapeutic relevance of this signaling axis in LUAD.
    Keywords:  CCT2; CCT7; DR5; JNK; PD-L1; c-Jun
    DOI:  https://doi.org/10.3390/cells15171613
  67. Int J Mol Sci. 2026 Sep 03. pii: 7882. [Epub ahead of print]27(17):
    The RNA-Binding Protein ELAVL4/HuD Promotes Stress-Associated Tumor Survival in Neuroendocrine Cancers.
    Kausik Bishayee, Vaishak Kaviyarasan, Sun Young Yoo, Seung Hee Lee, Yong Soo Park.
      Neuro-endocrine-related cancers overexpress ELAVL4 (HuD), a neuron-specific RBP implicated in post-transcriptional regulation. HuD plays a role in tumor cell survival; its knockdown in cancer cells and tumors leads to reduced growth and viability. In this review, we addressed HuD's role in several molecular pathways that contribute to the development of cancer. For example, cancer cells that have high levels of HuD are able to better withstand stressful tumor microenvironments because HuD stabilizes certain mRNAs, which promotes tumor development, modulates oxidative and metabolic stress, enhances autophagy, and impairs apoptosis. We discussed future studies on HuD in cancer, which should focus on its diverse roles in various cancer types and the molecular aspects. Furthermore, assessing HuD's contribution to the efficacy of immunotherapy requires an understanding of how it affects immune responses in malignancies. The development of targeted therapies, such as RNA-based approaches and small molecules, offers intriguing avenues for precision cancer management. The transition of HuD-directed therapies from preclinical models to clinical trials is anticipated to be accelerated by ongoing advancements in RNA-targeted drug discovery, structural biology, medicinal chemistry, and targeted drug delivery, even though no HuD-specific therapies have yet entered standard clinical practice.
    Keywords:  ARL6IP1; ELAVL4/HuD; GRB-10; cancer cell survival; mTORC1
    DOI:  https://doi.org/10.3390/ijms27177882
  68. Nat Commun. 2026 Sep 17. pii: 9882. [Epub ahead of print]17(1):
    Ashwin and FAM98 paralogs define nuclear and cytoplasmic RNA ligase complexes for tRNA biogenesis.
    Moritz Kleinwächter, Marius Moser, Nathan Raynaud, Moritz M Pfleiderer, Martin Jinek, Javier Martinez.
      The tRNA ligase complex (tRNA-LC) seals tRNA exon halves in the nucleus during pre-tRNA splicing and XBP1-mRNA exons in the cytoplasm as part of the unfolded protein response (UPR). This dual function requires the tRNA-LC to be either nuclear or cytoplasmic. Here, we reveal that Ashwin (ASW), the vertebrate-specific subunit of the tRNA-LC, serves as its nuclear import factor. ASW contains a dual nuclear localisation signal (NLS) which, upon disruption, leads to the retention of the tRNA-LC in the cytoplasm, impairing pre-tRNA splicing with the consequent accumulation of 5' tRNA fragments. We also show that the tRNA-LC exists in three forms, depending on which FAM98 paralog is bound, either FAM98A, FAM98B or FAM98C. ASW interacts exclusively with the FAM98B-containing complex, ensuring its nuclear localization for tRNA biogenesis. Attaching an NLS to RTCB, the catalytic and indispensable tRNA-LC subunit, rescues pre-tRNA splicing in cells depleted of ASW. We hypothesize that vertebrates evolved ASW to localize a sub-population of tRNA-LC to the nucleus, while using FAM98 paralogs to retain a fraction of RTCB in the cytoplasm to splice XBP1-mRNA during UPR.
    DOI:  https://doi.org/10.1038/s41467-026-77451-x
  69. Biology (Basel). 2026 Sep 07. pii: 1562. [Epub ahead of print]15(17):
    Mitochondrial Remodeling, Cytoskeletal Dynamics, and Translational Control During Drosophila Spermatid Elongation: An Integrative Review.
    Yang Fang, Jiaxin Yin, Liping Chen, Fengchao Zhang, Yang Liu, Liang Ma, Xiwen Liu, Yang Luo, Hua He, Qijun Xie.
      Spermatogenesis in Drosophila melanogaster is a classical model for studying cell polarity establishment, organelle remodeling, and extreme cellular morphogenesis. Spermatid elongation involves a series of highly coordinated dynamic events, including nuclear polarization, axonemal extension, mitochondrial remodeling, and individualization-mediated cytoplasmic clearance. Current studies have largely focused on individual structures, molecules, or pathways, resulting in a fragmented understanding of this process and a lack of an integrated framework that links mitochondrial function, cytoskeletal dynamics, and temporal translational regulation. Based on existing evidence, this review organizes current findings into three regulatory layers involving mitochondrial remodeling, cytoskeletal dynamics, and post-transcriptional translational control. Mitochondrial remodeling provides structural and metabolic support for sperm-tail formation, cytoskeletal processes execute axoneme organization and individualization, and post-transcriptional regulation controls the timing of protein production. Experimental evidence is strongest for mechanisms operating within each layer, whereas direct molecular coupling among the three layers remains incompletely established. We therefore present this model as a working framework rather than an established causal pathway. This framework helps organize current knowledge of extreme cellular differentiation and provides a basis for comparative studies of spermatogenesis and selected mechanisms associated with human male infertility.
    Keywords:  Drosophila melanogaster; cytoskeletal dynamics; individualization; mitochondrial remodeling; post-transcriptional regulation; spermatid elongation
    DOI:  https://doi.org/10.3390/biology15171562
  70. Mol Ther Nucleic Acids. 2026 Sep 08. 37(3): 103066
    PCBP2 facilitates miR-93-5p-mediated repression of GDF11 in HCC cell lines.
    Jemin Kim, Soyoung Kim, Minhyuk Yoon, Seung Joon Baek, Chanseok Shin.
      Growth differentiation factor 11 (GDF11), a member of the transforming growth factor-β superfamily, functions in skeletal muscle and neuronal regeneration and has been implicated in tumor suppression. In hepatocellular carcinoma (HCC), GDF11 expression is markedly downregulated, but the mechanisms responsible for this repression remain unclear. In this study, we examined whether the oncogenic miR-106b-25 cluster contributes to GDF11 suppression in HCC. We found that this cluster decreases GDF11 expression at both the mRNA and protein levels, with miR-93-5p acting as the dominant regulator. Inhibition of miR-93-5p with antisense oligonucleotides restored GDF11 expression and reduced HCC cell proliferation, migration, and invasion. Mechanistically, we identified the RNA-binding protein (RBP) PCBP2 as a key facilitator of miR-93-5p targeting of GDF11. PCBP2 binds a C-rich element adjacent to the miR-93-5p target site in the GDF11 3' UTR, thereby enhancing miR-93-5p-mediated repression. PCBP2 knockout attenuated miR-93-5p-mediated repression, whereas re-expression of PCBP2 restored it, supporting its modulatory role. Collectively, these findings identify PCBP2 as a modulator of miR-93-5p-mediated GDF11 repression and suggest that this regulatory interaction contributes to HCC cell proliferation, migration, and invasion. This work provides insights into the post-transcriptional control of the tumor suppressor and highlights the therapeutic potential of targeting miRNA-RBP interactions.
    Keywords:  GDF11; MT: non-coding RNAs; PCBP2; RNA-binding protein; RNA-protein interaction; hepatocellular carcinoma; microRNA-93-5p
    DOI:  https://doi.org/10.1016/j.omtn.2026.103066
  71. Pharmacol Res. 2026 Sep 14. pii: S1043-6618(26)00372-5. [Epub ahead of print] 108457
    Decoding oxidative stress-driven metabolic reprogramming in skeletal degenerative diseases: natural phytochemicals as precision metabolic modulators.
    Ruoping Yanzhang, Jiayi Guo, Zhaojie Yang, Youwen Liu, Huijun Zhang, Yin Yu, Xiaolong Wu, Hongting Jin, Chen Yue.
      Skeletal degenerative diseases are prevalent chronic disorders associated with aging. Oxidative stress promotes metabolic reprogramming in bone, cartilage, and intervertebral disc cells; however, the underlying mechanisms remain incompletely understood. Plant-derived phytochemicals may suppress oxidative stress and regulate metabolic reprogramming, thereby offering potential therapeutic benefits. In this review, we summarize oxidative stress-induced alterations in mitochondrial function and glucose, lipid, and amino acid metabolism across major skeletal degenerative diseases and discuss the therapeutic effects of natural phytochemicals that attenuate oxidative stress and modulate these metabolic changes. Clinical translation remains limited by three major challenges: the lack of validated biomarkers, inadequate patient stratification, and inefficient delivery systems. Potential strategies to address these challenges include biomarker-guided patient selection, the development of more physiologically relevant experimental models, and dynamic study protocols, which may facilitate the translation of basic research findings into clinical practice.
    Keywords:  adaptive clinical trials; metabolic reprogramming; mitochondrial dysfunction; natural phytochemicals; oxidative stress; precision medicine; skeletal degenerative diseases
    DOI:  https://doi.org/10.1016/j.phrs.2026.108457
  72. Proc Natl Acad Sci U S A. 2026 Sep 22. 123(38): e2613102123
    Bacterial stress responses lower mRNA-protein level correlations.
    Sena G Süer, Jérôme Arnoux, Yi Y Lim, Ganeshwari Dhurve, Rabia Şen, Cemal Erdem, André Mateus, Kemal Avican.
      Diverse bacterial pathogens have evolved complex regulatory mechanisms to adapt to various environmental stresses during infection. The uncertainty in mRNA-protein levels in response to environmental stressors complicates our understanding of bacterial physiology and their adaptation to stressful environments. To examine this issue, we have integrated transcriptomics and proteomics data on three human bacterial pathogens: Salmonella enterica Typhimurium, Yersinia pseudotuberculosis, and Staphylococcus aureus under 10 infection-relevant stress conditions. We observed positive correlations between mRNA and protein levels, which were decreased under different stress conditions. Essential genes exhibited higher expression levels with lower variation across the conditions and stronger mRNA-protein correlations compared to nonessential genes, highlighting their critical role in bacterial adaptability and survival. Moreover, we identified a substantial number of genes with stress-induced noncorrelating mRNA-protein levels, particularly under conditions triggering strong stress responses. Particularly this level was dramatically lowered for osmotic stress-specific genes affected by impaired translational activity under osmotic stress. Our findings highlight the prevalence of noncorrelating mRNA-protein levels and the potential role of posttranslational modifications in modulating protein levels in response to environmental stressors during infection. This study provides a comprehensive framework for integrating transcriptomics and proteomics data and identifies potential gene products that might significantly impact the ability of diverse bacterial pathogens to adapt to hostile infection environments.
    Keywords:  bacteria; data integration; mRNA; protein; stress response
    DOI:  https://doi.org/10.1073/pnas.2613102123
  73. Front Cell Dev Biol. 2026 ;14 1939490
    Lactate-driven lactylation reprograms chondrocyte fate and joint inflammation in osteoarthritis: linking metabolism with epigenetic regulation.
    Xinyu Liu, Kangyi Hu, Dengyan Bai.
      The sustained progression of osteoarthritis (OA) arises not only from mechanical injury and inflammatory stimulation but also from the gradual loss of chondrocyte homeostatic identity. However, a unifying mechanism explaining how metabolic abnormalities within the joint microenvironment are converted into relatively stable degenerative programs remains lacking. The discovery of lactylation provides a new perspective on this question. OA-associated hypoxia, inflammation, and aberrant mechanical loading can promote glycolytic reprogramming and lactate accumulation, while lactate further channels metabolic stress into chromatin regulation and protein functional networks through histone and non-histone lactylation. Current evidence suggests that this process does not merely amplify a single catabolic pathway, but reshapes chondrocyte fate at multiple levels by impairing matrix-maintaining capacity, driving the transition from a homeostatic phenotype toward catabolic, fibrotic, and senescent states, and altering cellular susceptibility to oxidative injury and pathological cell death. Meanwhile, metabolic reprogramming in synovial cells and immune cells may expand the intra-articular lactate pool, thereby linking intracellular lactylation changes with inter-tissue inflammatory crosstalk. Notably, the effects of lactylation are not uniformly pathogenic, but depend on the modified site, protein substrate, cellular state, redox environment, and disease stage. This bidirectionality is evident in both histone and non-histone lactylation: UGDH K6 lactylation and selected H3K18la-associated programs are linked to matrix damage and fibrotic phenotypes, whereas H3K56la may preserve COL2A1 expression and enhance chondrocyte stress adaptation under specific post-traumatic and redox conditions. Lactylation is therefore better understood as a metabolic state-driven "fate code" rather than a passive marker of lactate accumulation. This review integrates the continuum linking lactate metabolism, site-specific lactylation, and chondrocyte fate remodeling, with particular emphasis on matrix homeostasis, cellular senescence, survival-death transitions, and the inflammatory microenvironment. It also discusses the therapeutic implications of shifting from global modulation of lactylation toward cell- and site-specific intervention. This framework may deepen our understanding of OA chronicity and provide a theoretical basis for metabolic phenotype stratification and disease-modifying therapy.
    Keywords:  chondrocyte; lactate; lactylation; metabolic reprogramming; osteoarthritis
    DOI:  https://doi.org/10.3389/fcell.2026.1939490
This page is being maintained by Thomas Krichel. It was last updated on 2026‒09‒20 at 6:55.