bims-ribost Biomed News
on Ribostasis and translation stress
Issue of 2026–07–26
sixty-nine papers selected by
Cédric Chaveroux, CNRS
  1. Selective Reprogramming of Ribosome Assembly and Translational Control during Bacterial Growth Phase Transitions.
  2. Upstream non-AUG initiation and ribosomal -1 frameshifting in ATXN8OS CTA/CTG repeat-associated translation.
  3. FMRP regulates neuronal RNA granules containing stalled ribosomes, not where ribosomes stall.
  4. The protein kinase GCN2 senses the integrity of the multi-tRNA synthetase complex.
  5. Position-dependent codon occurrence is associated with patterns of translational efficiency and ribosomal occupancy in the human transcriptome.
  6. m6A RNA methylation modulates IFN-γ-stimulated intestinal epithelial cell-intrinsic antiparasitic defense.
  7. Transfer RNA expression, modification, and derived small RNAs in cancer biology and clinical potential.
  8. Nascent chain folding status modulates ribosome dynamics and mRNA stability through the ribosome-associated chaperone Zuo1.
  9. Mitochondrial translation termination, recycling, reinitiation, and rescue for in-frame and out-of-frame contexts.
  10. Ribosome biogenesis in osteoarthritis: mechanisms and therapeutic potential.
  11. Interplay between N6-methyladenosine RNA methylation and protein lactylation: a novel crosstalk linking metabolism and epigenetic regulation in human diseases.
  12. Downregulation of mTORC1 Signaling is Associated with Increased Sensitivity to Protein Synthesis Perturbations in Multiple Myeloma.
  13. Differential assembly of RNP granules via activation of distinct dsRNA sensors by adenovirus mutants.
  14. Metabolically induced intestinal inflammation: the role of ER stress and autophagy in a porcine model of diabetes.
  15. The ubiquitin system in heart and vessel pathobiology: From mechanisms to therapeutic strategies.
  16. Toward a comprehensive modification landscape of yeast mitochondrial tRNAs using Nanopore direct RNA sequencing and dihydrouridine sequencing.
  17. Editorial: Harnessing the power of small RNAs: advances and applications in plant gene silencing and stress response.
  18. Mitochondrial RNA modifications in gene expression and cancer biology.
  19. Translational resistance to amino acid starvation in breast cancer cells revealed by ribosome profiling.
  20. Structural adaptations for enhanced translation kinetics in evolved ribosomes.
  21. RSK signaling in myeloid malignancies: biology, disease dependency, and therapeutic targeting.
  22. ETTAS: a modular aptamer-recruited platform for programmable translational activation.
  23. Photoperiodic patterns in miRNA-mRNA pairs and tRNA fragments revealed by time-course co-sequencing in Arabidopsis.
  24. RNA epitranscriptomic regulation of tumor immune evasion: mechanisms, context-dependent roles, and therapeutic implications.
  25. Interplay Between DNA and RNA Methylation Shapes Cancer Cell Plasticity.
  26. METTL1/WDR4 Complex: A Novel Epitranscriptomic Target at the Crossroads of RNA Methylation and Drug Discovery.
  27. Acupuncture-induced HSP70 upregulation in neuroprotection: mitochondrial and anti-apoptotic mechanisms.
  28. Post-transcriptional regulation of light-stress responses and predictive modeling in vegetable Solanaceae Crops.
  29. Organization of Ribosomal RNA Genes in Eukaryotes.
  30. Phytochemicals modulating HSF-1-associated pathways: A systematic review of longevity-extending mechanisms in Caenorhabditis elegans.
  31. m6A RNA modification: a central epitranscriptomic switch orchestrating oncogenic signaling and glycolytic reprogramming in cancer.
  32. Dietary modulation of CMA: implications for cancer prevention and therapy.
  33. Impaired mitochondrial quality control and stress signalling machinery modulate senescence induction by genotoxic challenge.
  34. G3BP1 methylation by PRMT5 facilitates its recruitment of TBK1 for IRF3 activation during host response to foreign ribonucleic acids.
  35. A haloarchaeal VapBC toxin-antitoxin system: regulatory mechanism and role in establishing population heterogeneity to facilitate survival of subpopulations under stress conditions.
  36. ER stress-dependent Ddit4/REDD1 induction contributes to translational suppression during cisplatin-induced skeletal muscle atrophy.
  37. DDX3X syndrome mutations lock DDX3X-RNA conformational states to drive persistent pathological condensation and neuronal death.
  38. RNA quality control enables antibiotic tolerance.
  39. Proteome analyses reveal endoplasmic reticulum stress-induced changes in protein abundance associated with Ube2j2 deficiency in human cell culture.
  40. Is Nuclear mTOR Relevant for Neuronal Dysfunction?
  41. Phosphorylation networks as regulatory hubs in plant stress signaling: kinase dynamics, crosstalk, and network plasticity.
  42. Transcriptional reprogramming of the stress response and translational-secretory machinery enhances recombinant secreted protein production in Yarrowia lipolytica.
  43. RNA modifications in radiotherapy resistance and radiosensitization: epitranscriptomic regulation of tumor response to radiation.
  44. DB-IRES: a deep learning model based on ensemble learning for predicting internal ribosome entry sites.
  45. Conformational and Functional Divergence of RnpA Protein Subfamilies in Bacterial Ribonucleoprotein RNase P.
  46. FUBP3 regulates expression and alternative splicing of genes associated with cell proliferation and apoptosis in cancer cells.
  47. Systematic comparison of temporal hepatotoxicant-induced gene network responses across three liver test systems.
  48. The PERK paradox in aging: how ER stress shapes senescence and neurodegeneration.
  49. Nuclear Stress Bodies and Mitochondrial Signal Transduction Regulate Thermotolerance in Cattle: Insights Into Molecular Mechanisms.
  50. The m6A Reader IGF2BP2 Suppresses Ferroptosis in Nasopharyngeal Carcinoma by Stabilizing NRF2 mRNA.
  51. A novel RNA-binding activity of ECD contributes to U5 snRNP stability and pre-mRNA splicing.
  52. APE1/Ref-1: multifunctional biology, selective inhibition, and the path to clinical translation.
  53. Orchestration of OXPHOS biogenesis through regulation of mitochondrial translation.
  54. TAF7 accumulates in the cytoplasm during cellular transformation and engages STAT3, WASH, and CCT.
  55. Activity-dependent ribosome profiling reveals the landscape of canonical and non-canonical translation in brain tissue.
  56. Dual regulation of the unfolded protein response by IGF2BP3 during ER stress.
  57. Post-translational modification of proteins in the human testis development pathway.
  58. The Piezo1/YAP mechanotransduction axis: From mechanistic insights to therapeutic perspectives in disease.
  59. qMAP decodes RNA fragmentation dynamics in development and disease.
  60. Mitochondrial tRNA biogenesis, modifications and disease relevance.
  61. Plasma amino acid fluctuations in response to acute psychosocial stress among healthy adults with and without early-life adversity.
  62. Global Changes in Unproductive Splicing and NMD Efficiency in Tumors.
  63. A multiscale model reveals how ERK/p38-regulated dormancy shapes tumor-immune dynamics and immunoediting outcomes.
  64. N6-methyladenosine-mediated upregulation of PAICS promotes lung-adenocarcinoma metastasis via the integrin-FAK signaling.
  65. Structural dynamics of IRE1 and its interaction with unfolded peptides.
  66. Microprotein MP104 Promotes Malignant Progression of Colorectal Cancer Through Regulating Protein Translation.
  67. Hdac3 suppresses apoptosis through deacetylating and stabilizing the antiapoptotic protein Diap1.
  68. Annulate lamellae - an underexplored cellular structure.
  69. Mechanistic analysis and clinical translation strategies of m6A erasers in the metabolism-immunity axis of hepatocellular carcinoma.
  1. ACS Omega. 2026 Jul 21. 11(28): 41479-41489
    Selective Reprogramming of Ribosome Assembly and Translational Control during Bacterial Growth Phase Transitions.
    Manuel Terrazas-López, Vanessa Aitken, Tonya N Zeczycki, Eda Koculi.
      Most bacteria in natural environments experience prolonged nutrient limitation resembling the stationary phase and only intermittently encounter nutrient-rich conditions analogous to exponential growth. Understanding the molecular processes operating in these two states is therefore essential for elucidating bacterial adaptation to fluctuating nutrient availability. We applied a label-free proteomics workflow to characterize protein-level differences in the Escherichia coli (E. coli) proteome between exponential and prolonged stationary growth phases. We found that multiple components of the translational machinery are selectively enriched during the exponential growth. These include the DEAD-box rRNA (rRNA) chaperones DeaD, DbpA, and RlhE, the small-subunit ribosomal protein chaperone RimP, and 13 ribosomal proteins, several of which possess RNA and/or combined RNA-protein chaperone activity. In addition, enzymes responsible for post-transcriptional modification of rRNA and tRNA, RlmN, RsmI, RluB, RlmG, and TsaC, were more abundant during exponential growth, consistent with enhanced ribosome stability, translation rate, and translational fidelity under conditions of rapid proliferation. Translation initiation factors IF-1 and IF-3 and the elongation factor EF-P, which support efficient translation initiation and alleviate ribosomal stalling on challenging sequences, were also elevated during the exponential phase. Finally, a distinct set of proteins associated with antibiotic response exhibited differential abundance between exponential and stationary growth phases, indicating growth phase-dependent remodeling of cellular stress and defense pathways. Together, these findings provide a statistically supported, protein-level framework that defines how specific components of the translational machinery are selectively remodeled during the transition between exponential and stationary growth phases in E. coli, with potential relevance to other bacteria.
    DOI:  https://doi.org/10.1021/acsomega.6c00334
  2. Nucleic Acids Res. 2026 Jul 17. pii: gkag730. [Epub ahead of print]54(14):
    Upstream non-AUG initiation and ribosomal -1 frameshifting in ATXN8OS CTA/CTG repeat-associated translation.
    Soyoka Sakamoto, Hayato Ito, Mayuka Hasumi, Tatsuya Morisaki, Makito Hirano, Tatsuya Niwa, Yoshitaka Nagai, Timothy J Stasevich, Hideki Taguchi.
      Microsatellite repeat expansions contribute to the pathogenesis of many neurodegenerative disorders. In spinocerebellar ataxia type 8 (SCA8), abnormal expansion of CTA/CTG repeats in the 3' untranslated region of the ATXN8OS (ATXN8 Opposite Strand) gene has been implicated in disease pathology. Although the occurrence of repeat-associated non-AUG (RAN) translation from the ATXN8 transcript has been reported, whether and how RAN translation occurs from the ATXN8OS transcript has remained unexplored. Here, using a cell-free translation system and cultured cells, we showed that ATXN8OS undergoes robust AUG-independent translation in a repeat length-dependent manner. Mechanistic analyses revealed that translation of the poly L (0) frame initiates at a non-AUG codon located upstream of the repeats. Moreover, using live-cell imaging at a single messenger RNA level, we directly visualized ribosomal -1 frameshifting from the poly L (0) frame to the poly T-poly A (+2) frame during translation elongation. We further showed that ATXN8OS translation was enhanced upon activation of the integrated stress response. Together, these findings establish both the occurrence and the molecular mechanisms of ATXN8OS translation from expanded CTA/CTG repeats and provide insights into the pathogenic processes underlying SCA8.
    DOI:  https://doi.org/10.1093/nar/gkag730
  3. Elife. 2026 Jul 20. pii: RP106692. [Epub ahead of print]14
    FMRP regulates neuronal RNA granules containing stalled ribosomes, not where ribosomes stall.
    Jewel T-Y Li, Mehdi Amiri, Senthilkumar Kailasam, Lily Drever, Jingyu Sun, Laura Bohorquez, Nahum Sonenberg, Joaquin Ortega, Wayne S Sossin.
      Local protein synthesis is a crucial process that maintains local proteostasis in neurons. A large percentage of mRNAs translated in developing neurons are associated with stalled ribosomes. FMRP, the protein lost in Fragile X syndrome, is highly enriched in RNA granules that contain stalled ribosomes. Previous examination of ribosome-protected fragments (RPFs) from stalled neuronal ribosomes identified sequences that match those found in mRNAs associated with FMRP. To investigate whether FMRP recognition of these sequences is important for determining where ribosomes stall on mRNAs, we examined RPFs isolated from P5 mice of both sexes that lack the FMRP protein. The loss of FMRP had no significant effect on the proteins associated with neuronal stalled ribosomes, on ribosome structure, or the stalling sites (locations where RPFs accumulated). There was a small, but significant decrease in the number of RPFs from mRNAs previously shown to be associated with FMRP by CLIP. Additionally, the number of neuronal RNA granules containing stalled ribosomes, as assayed by ribopuromycylation, decreased. These results suggest a role of FMRP in neuronal RNA granules that contain stalled ribosomes, though loss of FMRP does not influence where ribosomes are stalled or the formation of stalled ribosome.
    Keywords:  FMRP; RNA binding protein; RNA granule; cell biology; mouse; neuroscience; ribopuromycylation; ribosome-protected fragment; stalled ribosome
    DOI:  https://doi.org/10.7554/eLife.106692
  4. Biochem Biophys Res Commun. 2026 Jul 16. pii: S0006-291X(26)01037-5. [Epub ahead of print]831 154273
    The protein kinase GCN2 senses the integrity of the multi-tRNA synthetase complex.
    Richard Cardoso da Silva, Beatriz A Castilho.
      Aminoacyl-tRNA synthetases (ARSs) assemble with ARS-interacting multifunctional proteins (AIMPs) to form the multi-tRNA synthetase complex (MSC), a supramolecular complex proposed to enhance efficiency of tRNA aminoacylation. Here, we show that disassembly of MSC via siRNA-mediated depletion of the scaffold protein AIMP2 promotes a transient activation of the eIF2α kinase GCN2 in mouse embryonic fibroblasts (MEFs). Activation of GCN2 was accompanied by increased eIF2α phosphorylation, induction of ATF4, and attenuation of global protein synthesis. Importantly, these effects were abolished in Gcn2-/- MEFs, indicating that translational repression following MSC disassembly is largely dependent on GCN2. Notably, GCN2 activation and eIF2α phosphorylation were induced at early time points and resolved by 24h following AIMP2 depletion and progressively resolved despite sustained suppression of AIMP2 expression, suggesting adaptive restoration of translational homeostasis. Together, our findings link disruption of MSC integrity to the GCN2-dependent integrated stress response and support a functional link between higher-order organization of the translational machinery and cellular stress sensing.
    Keywords:  AIMP2; GCN2; Multi-tRNA synthetase complex; Translation initiation; eIF2α
    DOI:  https://doi.org/10.1016/j.bbrc.2026.154273
  5. PLoS Comput Biol. 2026 Jul;22(7): e1014501
    Position-dependent codon occurrence is associated with patterns of translational efficiency and ribosomal occupancy in the human transcriptome.
    Kaavya Subramanian, Nathan Waugh, Cole Shanks, David A Hendrix.
      All life depends on the reliable translation of RNA to protein according to complex interactions between translation machinery and RNA sequence features. While ribosomal occupancy and codon frequencies vary across coding regions, well-established metrics for computing coding potential of RNA do not capture such positional dependence. Here, we investigate positional bias in codon usage, which contextually accounts for the position of protein-coding signals embedded within coding regions. We demonstrate the existence of position-dependent patterns of codon frequency in the human transcriptome and describe these patterns using our POsition-Specific Codon Occurrence (POSCO) score that is more consistently associated with translation-initiating codons than other common sequence features. We further show that the patterns described by POSCO are not accounted for by other common scores, including position-dependent GC content, consensus sequences, and the presence of signal peptides in the translation product. More importantly, POSCO defines a spectrum of translational efficiency and local tRNA adaptation index (tAI). High POSCO scores correspond to the highest initial tAI values, which increase over the downstream length of the transcript, forming a translational highway. Meanwhile, low POSCO scores exhibit the lowest initial tAI values followed by a previously undescribed translational valley. An inverse correlation was found between POSCO score and ribosomal occupancy near the start codon. We also find that POSCO defines a spectrum of local folding energies, with high-POSCO transcripts showing the most stable folding immediately after the start codon. Finally, we examine the relationship between POSCO intensity and functional enrichment. We find that transcripts with start codons showing the highest POSCO are enriched for functions relating to development of musculoskeletal, cardiovascular, neurological, gastrointestinal, sensory, and other body systems. Furthermore, transcripts with high POSCO are depleted for functions related to immune response and detection of chemical stimulus. These findings lay important groundwork to improve our understanding of the regulation of translation, the calculation of coding potential, and the classification of RNA transcripts.
    DOI:  https://doi.org/10.1371/journal.pcbi.1014501
  6. PLoS Pathog. 2026 Jul;22(7): e1014442
    m6A RNA methylation modulates IFN-γ-stimulated intestinal epithelial cell-intrinsic antiparasitic defense.
    Chansorena Pok, Ai-Yu Gong, Marion L Graham, Shuhong Wang, Silu Deng, Zinat Sharmin, Eugene Lu, Guoqing Lu, Chuan He, Xian-Ming Chen.
      N6-methyladenosine (m6A) RNA methylation is one of the most prevalent reversible post-transcriptional RNA modifications and has been recognized as a crucial regulator of host immune responses. Intestinal epithelial cells (IECs) constitute an important component of gastrointestinal mucosal immunity. Interferons (IFNs) play a central role in maintaining intestinal homeostasis, and m6A methylation status influences IFN-mediated cell-intrinsic defense. In this study, we investigated the potential role of m6A RNA modifications in IFN-γ-stimulated IEC-intrinsic defense. We observed significant alterations in the topology of the m6A mRNA methylome in murine IECs following IFN-γ stimulation. A subset of IFN-γ-stimulated immune gene transcripts exhibited increased m6A RNA methylation, including several members of the immunity-related GTPase family M (IRGM) genes. In addition, IFN-γ-responsive long non-coding RNAs may modulate the m6A methylation levels of multiple IFN-γ-stimulated immune transcripts. Enhanced m6A methylation of the Irgm2/3 transcripts was associated with strengthened cell-intrinsic defense against infection by the protozoan parasite Cryptosporidium. Notably, Cryptosporidium infection altered the host m6A mRNA methylome in IECs, thereby counteracting the IFN-γ-mediated defense response. Although the RNA levels of Irgm2/3 genes were upregulated, their m6A RNA methylation levels and protein expression were reduced in infected cells. This effect was associated with host delivery of dsRNAs derived from Cryptosporidium parvum virus 1, a virus harbored in the parasite. Collectively, our findings suggest that m6A methylation of RNA transcripts enhances IFN-γ-mediated IEC-intrinsic antiparasitic defense, while Cryptosporidium has evolved mechanisms to evade this response by suppressing m6A RNA methylation of IFN-γ-stimulated immune genes.
    DOI:  https://doi.org/10.1371/journal.ppat.1014442
  7. Front Immunol. 2026 ;17 1733897
    Transfer RNA expression, modification, and derived small RNAs in cancer biology and clinical potential.
    Ming Luo, Ji'an Liu, Yang Su, Rao Fu, Xufeng Huang, Qi Wang, Jing Li, Zhengrui Li, Li Liu.
      Transfer RNA (tRNA) is essential for protein synthesis and undergoes diverse chemical modifications that regulate its stability and function. Dysregulation of tRNA expression and modifications, along with the activity of tRNA-derived small RNAs (tsRNAs) and aminoacyl-tRNA synthetases, has been increasingly linked to cancer development, influencing tumor proliferation, metastasis, stress responses, and therapy resistance. Here we systematically review the biological features of tRNA and its modifications, elucidate their mechanistic roles in various cancers, and explore the emerging functions of tsRNAs and tRNA-modifying enzymes. We also assess the diagnostic and therapeutic potential of targeting tRNA pathways in oncology. These insights provide a foundation for advancing precision medicine approaches by exploiting tRNA-related mechanisms to improve cancer diagnosis and treatment outcomes.
    Keywords:  aminoacyl-tRNA synthetase; tRNA modifications; tRNA-derived fragments; therapeutic targets; transfer RNA; tumor biomarkers
    DOI:  https://doi.org/10.3389/fimmu.2026.1733897
  8. Mol Cell. 2026 Jul 22. pii: S1097-2765(26)00457-0. [Epub ahead of print]
    Nascent chain folding status modulates ribosome dynamics and mRNA stability through the ribosome-associated chaperone Zuo1.
    Suhee Chang, Ryan Kawalerski, Mehmet Tardu, Sophie Martin, Kristin S Koutmou, Jeff Coller.
      Ribosome dynamics during mRNA translation elongation regulate mRNA stability. Yet, known regulators of ribosome transit, such as codon usage, cannot fully explain transcriptome-wide decay rates. Here, we demonstrate that nascent polypeptide folding modulates elongation rates, with Zuotin (Zuo1) serving as an essential mediator. Using reporter constructs encoding co-translationally unstructured proteins and RNA sequencing under proteotoxic stress, we show that Zuo1 is required for selective destabilization of transcripts whose nascent peptides fail to fold properly. This process relies on the co-translational mRNA decay factor Not5, which detects slowed ribosomes. 35S labeling indicates that nascent peptide folding defects correlate with reduced elongation rates in a Zuo1-dependent manner, and ribosome profiling reveals that global protein misfolding induces Zuo1-dependent ribosome pausing. These findings position Zuo1 as a key mediator linking nascent peptide folding status to ribosome dynamics and mRNA stability. Furthermore, this work suggests an expanded role for Not5 beyond codon optimality sensing.
    Keywords:  Not5; Zuo1; elongation rate; mRNA degradation; mRNA stability; post-transcriptional regulation; protein chaperones; protein folding; ribosome speed
    DOI:  https://doi.org/10.1016/j.molcel.2026.06.041
  9. Nat Commun. 2026 Jul 21. pii: 6128. [Epub ahead of print]17(1):
    Mitochondrial translation termination, recycling, reinitiation, and rescue for in-frame and out-of-frame contexts.
    Taisei Wakigawa, Mari Mito, Qi Fang, Yuzuru Itoh, Yoichi Shinkai, Shintaro Iwasaki.
      Because mitochondria diverged from a bacterial ancestor during evolution, the mitochondrial protein synthesis system includes both mRNAs and translation factors with unique characteristics. However, the molecular mechanisms underlying translation termination, recycling, and quality control remain unclear. Here, via high-resolution mitochondrial Ribo-Seq and Disome-Seq, we reveal: the specificity of release factors for different kinds of stop codons; the role of mtRF1 in vertebrates, which do not have noncanonical stop codons in their main translons; the recycling-coupled translation of internal translons; and the rescue of mitoribosomes in the early elongation stage. mtRF1L recognizes all stop codons, whereas mtRF1 recognizes only AGA/AGG noncanonical stop codons. Additionally, mtRF1 terminates the translation of out-of-frame translons that end with AGA/AGG. We also found that mtRRF and mtIF3 are required for mitoribosome recycling on stop codons and for the reinitiation of internal translon translation. Mitoribosomes that stall at the start codons and/or at the early elongation phase are major substrates of the rescue factors ICT1, mtRF-R, and mtRES1. Moreover, HEMK1-mediated methylation of release factors enhances the termination reaction on stop codons. Our results provide insights into the mitoribosome dynamics that are associated with the completion of protein synthesis.
    DOI:  https://doi.org/10.1038/s41467-026-75248-6
  10. J Transl Med. 2026 Jul 18.
    Ribosome biogenesis in osteoarthritis: mechanisms and therapeutic potential.
    Zewen Xu, Zhiwei Pei, Haobo Yang, Shanjie Guo, Qiang Li, Liuchang Jiang, Jing Wang, Leipeng Wang, Dexin Liu, Xuanyin Chen, Baoxin Zhang, Ting Hao.
       BACKGROUND: Ribosomes are the core machinery for cellular protein synthesis, and defects in their biogenesis have been confirmed to be closely associated with various diseases. Osteoarthritis (OA), one of the most common joint diseases worldwide, has a complex pathogenesis that remains incompletely elucidated. Traditional research has primarily focused on metabolic imbalances in articular cartilage and inflammatory responses. However, growing evidence suggests that dysregulated ribosome biogenesis may play a critical role in the pathogenesis of OA. Impaired ribosome biogenesis limits the protein translation capacity of chondrocytes and may participate in the initiation and progression of OA by modulating cellular metabolism and stress responses, indicating that OA could be considered an acquired ribosomopathy.
    MAIN BODY: This review systematically summarizes the various factors involved in ribosome biogenesis and their impact on chondrocyte function and joint tissue homeostasis, with a particular focus on key molecules such as non-coding RNAs, ribosomal proteins, and translation regulators. By integrating the latest findings from in vivo and in vitro models, this work evaluates the potential therapeutic value of targeting ribosome biogenesis-related molecules for the treatment of OA.
    CONCLUSION: In summary, in-depth investigation of the role of ribosome biogenesis in OA may not only provide new perspectives for elucidating its pathological mechanisms but also offer a theoretical foundation and potential targets for developing therapeutic strategies that modify the disease course.
    Keywords:  Chondrocytes; Osteoarthritis; Protein translation; Ribosome biogenesis; Ribosomopathies
    DOI:  https://doi.org/10.1186/s12967-026-08679-w
  11. J Transl Med. 2026 Jul 20. pii: 945. [Epub ahead of print]24(1):
    Interplay between N6-methyladenosine RNA methylation and protein lactylation: a novel crosstalk linking metabolism and epigenetic regulation in human diseases.
    Yanyan Gong, Yu Liu.
      N6-methyladenosine (m6A) RNA methylation is the most prevalent internal modification in eukaryotic mRNA and precisely regulates gene expression by regulating the RNA life cycle. Lactate, a central glycolytic metabolite, can transduce cellular metabolic states into epigenetic signals through protein lactylation, an emerging post-translational modification. Because both modifications are highly responsive to cellular metabolic status, they have emerged as important regulators of the metabolic-epigenetic interface. Increasing evidence supports a bidirectional regulatory crosstalk between m6A modification and protein lactylation. Lactate accumulation can modulate the expression and activity of m6A-related regulatory enzymes through histone and non-histone lactylation; conversely, m6A modification can reshape glycolysis and lactate metabolism, thereby altering lactate availability and protein lactylation. This reciprocal regulation has been implicated in a broad spectrum of diseases, including cancer, metabolic disorders, cardiovascular diseases, and immune-inflammatory conditions. In this review, the molecular mechanisms of m6A modification and protein lactylation are systematically summarized, with particular emphasis on their modes of interaction and pathological relevance. Current limitations and future perspectives are also discussed, providing a conceptual framework for elucidating disease mechanisms and developing therapeutic strategies targeting this regulatory network.
    Keywords:  Epigenetics; Metabolism; Protein lactylation; m6A
    DOI:  https://doi.org/10.1186/s12967-026-08663-4
  12. ACS Omega. 2026 Jul 21. 11(28): 42076-42092
    Downregulation of mTORC1 Signaling is Associated with Increased Sensitivity to Protein Synthesis Perturbations in Multiple Myeloma.
    Didhiti Singha, Debopriya Choudhury, Meghna Mondal, Jahir Hossain, Brahmachari Vedeshachaitanya, Pushkar Malakar.
      Protein synthesis is critical for the survival and proliferation of multiple myeloma cells. mTORC1 signaling, through its downstream effectors S6K1 and S6, regulates ribosome biogenesis and protein homeostasis. However, the relative sensitivity of multiple myeloma cells to perturbations in protein synthesis compared with other cancer types remains unclear. In addition, the role of S6K1 and S6 signaling in the response to translational stress and the therapeutic potential of mTORC1 inhibition in multiple myeloma are not fully understood. Multiple myeloma and non-myeloma cancer cell lines were subjected to protein synthesis perturbations. Changes in mTORC1 signaling, including S6K1 and S6 activity, were analyzed. Cellular responses, including proliferation and apoptosis, were assessed. The mechanisms of protein synthesis were also evaluated under these conditions. The effects of the mTORC1 inhibitor Torin1 were examined across cell lines. Sensitivity to protein synthesis stress and mTORC1 inhibition was compared between multiple myeloma and other cancer types, including bortezomib-resistant cells. Multiple myeloma cell lines exhibited heightened sensitivity to protein synthesis perturbations, accompanied by marked suppression of S6K1 and S6 signaling and reduced global protein synthesis. This increased sensitivity resulted in decreased proliferation and increased apoptosis compared to non-myeloma cancer cell lines. Treatment with the mTORC1 inhibitor Torin1 produced a pronounced inhibitory effect in multiple myeloma cells. Notably, cell lines resistant to protein synthesis perturbations showed increased sensitivity upon mTORC1 inhibition. Furthermore, the bortezomib-resistant RPMI-8226 cell line was resensitized to bortezomib following Torin1 treatment. These findings establish a mechanistic link between mTORC1 signaling, protein synthesis stress, and multiple myeloma. Targeting mTORC1 signaling enhances sensitivity to translational stress and overcomes drug resistance, highlighting a potential therapeutic vulnerability in multiple myeloma.
    DOI:  https://doi.org/10.1021/acsomega.6c02288
  13. PLoS Pathog. 2026 Jul 24. 22(7): e1014452
    Differential assembly of RNP granules via activation of distinct dsRNA sensors by adenovirus mutants.
    Robert T Steinbock, Orlando B Scudero, Joseph M Dybas, Amber R N Abbott, Katarzyna Kulej, Richard Lauman, Holly Chan, Eva L Agostino, Namrata Kumar, Cameron Stone, Skyler Briggs, Nicholas A Parenti, Yize Li, James M Burke, Susan R Weiss, Alexander M Price, Matthew D Weitzman.
      Recognition of double-stranded RNA (dsRNA) triggers antiviral defense mediated by PKR and OAS3/RNase L pathways through translational arrest and RNA decay. This is accompanied by assembly of distinct cytoplasmic ribonucleoprotein (RNP) condensates termed stress granules (SGs) and RNase L-dependent bodies (RLBs). Here we show that adenovirus mutants engage distinct RNA-sensing pathways and promote differential assembly of cytoplasmic RNP granules. Infection with splicing-defective ∆E4 mutant leads to dsRNA accumulation and activation of both PKR and OAS3/RNase L, promoting formation of RLB-like granules. In contrast, mutants lacking virus-associated (VA) RNAs trigger PKR activation and assembly of SGs despite absence of detectable dsRNA. Proximity labeling proteomic analysis revealed distinct protein compositions of canonical SGs and RLBs, which were reflected in virus-induced granules. While ∆VA-induced granules were PKR-dependent, ∆E4 mutants induced RLB-like granules independently of PKR and RNase L. In cells lacking these sensors, granule assembly during ∆E4 infection coincided with translational arrest independent of eIF2α phosphorylation, indicating additional pathways linking nuclear dsRNA sensing to translational control and RNP granule assembly during viral infection. These findings provide novel insights into how distinct dsRNA sensors modulate translation and RNP condensates in response to stress.
    DOI:  https://doi.org/10.1371/journal.ppat.1014452
  14. Mol Cell Biochem. 2026 Jul 22.
    Metabolically induced intestinal inflammation: the role of ER stress and autophagy in a porcine model of diabetes.
    Ugljesa Malicevic, Ranko Skrbic, Devendra K Agrawal.
      The mechanisms linking chronic hyperglycemia to intestinal inflammation and epithelial dysfunction remain incompletely understood, highlighting an important gap in our understanding of diabetes-associated gastrointestinal pathology. In this study, we investigated the effects of sustained hyperglycemia on intestinal inflammation, endoplasmic reticulum (ER) stress, and autophagy in a translational porcine model of diabetes. Diabetes was induced in Yucatan mini pigs using a high-fat, high-carbohydrate/fructose diet (HFHFD) followed by streptozotocin administration. Intestinal tissues from the terminal ileum and sigmoid colon were analyzed using histological evaluation, quantitative real-time PCR, and immunohistochemistry. Histological analysis revealed structural alterations in diabetic animals, including villous degeneration, crypt depletion, goblet-cell loss, and increased inflammatory-cell infiltration. Gene expression analysis revealed significant upregulation of inflammatory mediators (NF-κB, TNF-α, IL-6, IL-1β), inflammasome components (NLRP3), and macrophage markers (CD68, CD86, CD163). In parallel, ER stress-related genes (ORMDL3, ATF6) and autophagy-associated genes (NOD2, ULK1, ATG4a) were significantly elevated in diabetic pigs. At the protein level, increased expression of ER stress markers was confirmed in both intestinal regions, while autophagy-related proteins showed less consistent changes and did not fully reflect the observed transcriptional patterns, suggesting a potential disconnect between transcriptional activation and downstream autophagy-related protein expression under diabetic conditions. Chronic hyperglycemia is associated with intestinal inflammation and disruption of cellular stress pathways, including ER stress and autophagy, in a porcine model. These findings provide mechanistic insight into how chronic hyperglycemia contributes to intestinal dysfunction through coordinated alterations in inflammatory signaling, ER stress, and autophagy pathways, identifying these processes as potential targets for therapeutic intervention in diabetes-associated gastrointestinal disease.
    Keywords:  Autophagy; Cytokines; ER stress; Hyperglycemia; Intestinal inflammation; Macrophage activation; Porcine model
    DOI:  https://doi.org/10.1007/s11010-026-05659-y
  15. Genes Dis. 2026 Nov;13(6): 102023
    The ubiquitin system in heart and vessel pathobiology: From mechanisms to therapeutic strategies.
    Jingjing Zhu, Zhimei Qiu, Yi Xu, Qing Guo, Shuangya Yang, Yongchao Zhao, Bei Shi.
      Cardiovascular disease is currently a major global challenge, and its causes are complex, encompassing genetic, lifestyle, environmental, and other factors. Ubiquitination, an important post-translational protein modification, is closely associated with cardiovascular disease and is involved in the regulation of protein degradation, signaling, and gene expression. An increasing number of studies have shown that ubiquitination plays a key regulatory role in the development and progression of cardiovascular disease. Recent research has elucidated the crucial role of ubiquitination modifications in governing various cellular processes, signaling pathways, and protein homeostasis within cardiovascular contexts. Specifically, these modifications have been implicated in cardiomyocyte injury and hypertrophy, macrophage inflammation, phenotypic changes in smooth muscle cells, and activation of fibroblasts. This review summarizes the role of ubiquitination modifications in recent years, focusing on the recognition of different substrate proteins by E3 ubiquitin ligases. These ligases are involved in the regulation of various cardiovascular disorders, such as atherosclerosis, myocardial ischemia/reperfusion injury, cardiac remodeling, cardiac arrhythmia, and hypertension. The findings provide new insights into the prevention and treatment of cardiovascular disease.
    Keywords:  Atherosclerosis; Cardiac remodeling; Deubiquitination; E3 ubiquitin ligase; Myocardial infarction; Post-translation modification; Ubiquitin proteasome system; Ubiquitination
    DOI:  https://doi.org/10.1016/j.gendis.2025.102023
  16. Nucleic Acids Res. 2026 Jul 17. pii: gkag736. [Epub ahead of print]54(14):
    Toward a comprehensive modification landscape of yeast mitochondrial tRNAs using Nanopore direct RNA sequencing and dihydrouridine sequencing.
    Julia L Reinsch, David M Garcia.
      Saccharomyces cerevisiae is an invaluable model in the study of mitochondrial tRNA biology. Yet the positions of modified bases in all yeast mitochondrially encoded tRNAs (mt-tRNAs) are still not fully mapped. We performed Nanopore direct RNA sequencing (DRS) on tRNAs from the crude mitochondrial fraction of yeast to map base modifications across all 24 mt-tRNA isoacceptors. Additionally, we adapted the "D-seq" method to detect dihydrouridine sites in tRNAs, where chemical reduction of dihydrouridine causes disruptions to reverse transcription. We mapped dihydrouridine, pseudouridine, and N2-dimethylguanosine sites in mt-tRNAs using DRS, tRNA-D-seq, and knockouts of five conserved tRNA-modifying enzymes. Our results establish Dus1 and Dus2 as the enzymes responsible for D14, D16, D17, D17a, and D20 formation in S. cerevisiae mt-tRNAs. We provide evidence of interactions between Dus1, Dus2, and Trm1-catalyzed modifications, and the influence of Ψ55 promoting m5U54 in mt-tRNAs. These findings expand our understanding of mt-tRNA base modifications and their interdependence, and advance opportunities for the yeast model to investigate defects in human mt-tRNA function.
    DOI:  https://doi.org/10.1093/nar/gkag736
  17. Front Plant Sci. 2026 ;17 1924418
    Editorial: Harnessing the power of small RNAs: advances and applications in plant gene silencing and stress response.
    Humberto Prieto, Álvaro Castro.
      
    Keywords:  RNA interference (RNAi); small RNAs (sRNAs); spray induced gene silencing (SIGS); stress response; systemic RNA mobility
    DOI:  https://doi.org/10.3389/fpls.2026.1924418
  18. MedScience. 2026 Jul 24.
    Mitochondrial RNA modifications in gene expression and cancer biology.
    Haixia Wang, Lili Ren, Dongling Zou, Rui Su.
      RNA modifications are essential in regulating gene expression at the post-transcriptional level. Recent studies, including our own, have highlighted that RNA modifications, such as N6-methyladenosine (m6A) and methyl-5-cytosine (m5C), play a crucial role in tumorigenesis, metabolism, and anti-tumor immunity. Targeting RNA modification machinery may represent a promising therapeutic strategy in cancer. Intriguingly, emerging evidence reveals numerous modifications in mitochondrial RNA (mt-RNA), expanding the concept of epitranscriptomics to mitochondria. The mammalian mitochondrion possesses its own genome, which encodes 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (rRNAs), and 13 proteins necessary for energy production via oxidative phosphorylation (OxPhos). The mitochondrial transcriptome is produced from large polycistronic transcripts, implying that mitochondrial gene expression is predominantly regulated post-transcriptionally. In this review, we summarize all currently known mt-RNA modifications, their potential regulatory machinery, as well as their biological functions in tumorigenesis and metabolism. Additionally, given that this field is still in its infancy, we discuss several critical knowledge gaps and propose future research directions to clarify the mechanistic and clinical significance in the study of mt-RNA modifications.
    Keywords:  RNA modifications; cancer; epitranscriptomics; metabolism; metastasis; mitochondria; tumor immunity
    DOI:  https://doi.org/10.1007/s11684-026-1233-z
  19. iScience. 2026 Jul 17. 29(7): 116627
    Translational resistance to amino acid starvation in breast cancer cells revealed by ribosome profiling.
    Fajin Li, Siqiong Zhang, Haoran Duan, Dieter A Wolf, Xuerui Yang.
      Translation elongation is highly sensitive to amino acid availability, with deprivation causing ribosome pausing at cognate codons, suppression of the mammalian target of rapamycin (mTORC1) signaling pathway, and GCN2-mediated phosphorylation of eIF2α. However, cell-type heterogeneity in these responses remains unclear. Integrating ribosome profiling datasets across over ten human cell lines and multiple starvation conditions, we uncover translational resistance in breast cancer cells specifically under leucine and glutamine deprivation. Unlike non-breast cancer cells, breast cancer cells maintain ribosome occupancy on mRNAs with a 5' terminal oligopyrimidine tract (5'TOP mRNAs), indicating sustained mTORC1 activity, and exhibit attenuated codon-specific pausing. GCN2-eIF2α pathway activation varies among breast cancer lines. Downregulation of the cystine/glutamate transporter SLC7A11 correlates with this resistance, and its overexpression restores sensitivity by reducing S6K phosphorylation while enhancing eIF2α phosphorylation. Our findings reveal that breast cancer cells adaptively reshape translation regulation to withstand amino acid starvation, highlighting a potential metabolic vulnerability.
    Keywords:  amino acid starvation; mTORC1; ribosome profiling; sensitivity; translation elongation
    DOI:  https://doi.org/10.1016/j.isci.2026.116627
  20. Nucleic Acids Res. 2026 Jul 17. pii: gkag703. [Epub ahead of print]54(14):
    Structural adaptations for enhanced translation kinetics in evolved ribosomes.
    Tushar Raskar, Alan Costello, Ahmed H Badran, James S Fraser.
      The ribosomal RNA sequence governs translation dynamics, yet understanding how changes beyond the conserved catalytic centers influence kinetics and protein yield remains limited. Using orthogonal ribosome phage-assisted continuous evolution, we recently reported chimeric ribosomes derived from Escherichia coli, Pseudomonas aeruginosa, and Vibrio cholerae endowed with elevated orthogonal translation activity as compared to their starting counterparts. Here, we structurally characterize these kinetically enhanced ribosomes using cryo-electron microscopy and uncover a potential relationship between 16S ribosomal RNA (rRNA) stability and translation efficiency. Compared to their naive starting points, evolved ribosomes exhibit extensive RNA structural adaptation, often introduced by mismatches at key helical junctions, which leads to local RNA-protein rearrangements and destabilizes non-canonical base pairs. Compensatory mutations that restore base-pairing stability and eliminate flexibility reduced translational activity to wild-type levels. Across trajectories, increased translational output correlates with subtle, localized changes in the 16S rRNA sequence that introduce limited structural destabilization at specific elements. Taken together, our work provides new insights into rRNA structural malleability and establishes principles for engineering ribosomes with altered translation properties.
    DOI:  https://doi.org/10.1093/nar/gkag703
  21. Front Cell Dev Biol. 2026 ;14 1900741
    RSK signaling in myeloid malignancies: biology, disease dependency, and therapeutic targeting.
    Gavin M Traber, Sandra E Dunn, Kathleen M Sakamoto.
      Acute myeloid leukemia (AML) and related myeloid malignancies remain clinically challenging despite recent advances in molecular profiling and targeted therapy. Although recurrent oncogenic drivers have improved disease classification and informed therapeutic development, durable disease control remains limited by signaling plasticity and therapeutic resistance of heterogeneous malignant stem and progenitor populations. These limitations drive continued interest in signaling dependencies that investigate oncogenic inputs across genetically diverse myeloid disease states. The p90 ribosomal S6 kinase (RSK) family has emerged as one such candidate. Positioned as a downstream convergence of MAPK/ERK and PI3K/PDK-1 signaling, RSK regulates proliferation, survival, translational control, inflammatory signaling, and cellular stress adaptation, all processes directly relevant to malignant progression. Growing evidence supports aberrant RSK activation in AML, functional dependency in FLT3-mutant AML and myeloproliferative neoplasms/myelofibrosis, and increasing translational interest in selective pharmacologic inhibition. Early preclinical studies demonstrate anti-leukemic activity through both genetic and pharmacologic targeting, while emerging clinical development of RSK inhibitors in solid tumors supports therapeutic feasibility. Here, we review the biologic role of RSK signaling in myeloid malignancies and discuss the therapeutic opportunities and challenges associated with targeting this signaling axis.
    Keywords:  acute myeloid leukemia; myeloproliferative neoplasms; ribosomal S6 kinase; signal transduction; targeted therapy
    DOI:  https://doi.org/10.3389/fcell.2026.1900741
  22. Nucleic Acids Res. 2026 Jul 17. pii: gkag692. [Epub ahead of print]54(14):
    ETTAS: a modular aptamer-recruited platform for programmable translational activation.
    Aolin Li, Xiaoting Zhang, Senmao Li, Yifan Wang, Chaojie Xu, Changning Lv, Min Zhao, Yuchen Liu, Mingxia Ding, Congcong Cao.
      Precise enhancement of endogenous protein synthesis offers a reversible therapeutic strategy without permanent genomic modification. However, existing Cas13-mediated translational activation systems are limited by modest potency and restricted modular expandability. Here, we developed the Enhanced Targeted Translational Activation System (ETTAS), a modular RNA-guided platform that combines dCas13a, the SINEB2 translational activation element, and an independently recruitable aptamer-mediated auxiliary module. Systematic ortholog screening identified dCas13a as the most effective scaffold for SINEB2-mediated translational activation, whereas direct tandem duplication of SINEB2 elements impaired rather than enhanced activity. To overcome this architectural limitation, we used aptamer-mediated recruitment to spatially separate target recognition from auxiliary activation. A binding-validated, non-interfering dCas13a-binding aptamer enabled construction of a dual-module system in which an aptamer-recruited SINEB2 element enhanced translation without altering target mRNA abundance or stability. Compared with the previously reported dCasRx-SINEB2 system, ETTAS produced stronger reporter activation, stronger endogenous induction of P53 and PTEN, and greater antiproliferative and pro-apoptotic effects in bladder cancer cells. Proteomic analyses showed selective target protein upregulation with limited global perturbation. In vivo, dual-AAV delivery of ETTAS activated endogenous P53 and suppressed tumor growth. ETTAS establishes a programmable framework for modular post-transcriptional upregulation of endogenous proteins.
    DOI:  https://doi.org/10.1093/nar/gkag692
  23. PLoS Genet. 2026 Jul;22(7): e1012229
    Photoperiodic patterns in miRNA-mRNA pairs and tRNA fragments revealed by time-course co-sequencing in Arabidopsis.
    Chun Chung Leung, Daniel A Tarté, Joshua M Gendron.
      In plants, the response to photoperiod is marked by global reprogramming of gene expression that drives extensive developmental changes. Small RNAs (sRNAs) play important roles in this process, but a comprehensive characterization of micro RNAs (miRNAs) and the more recently recognized transfer RNA fragments (tRFs) within this context is lacking. Herein, we characterize the patterns of miRNAs and tRFs in Arabidopsis by performing time-course sRNA-sequencing across three photoperiods. By comparing with our previous messenger RNA (mRNA) sequencing time-courses, we identified positively- or inversely-correlated miRNA-mRNA pairs between the two co-sequenced datasets that suggest photoperiodic sRNA regulations. Furthermore, we revealed 20 patterns of photoperiodic tRFs. These patterns are linked to the transfer RNA (tRNA) isotypes and positions they derive from, suggesting that tRFs are subjected to photoperiodic regulation. Finally, we present a major update to our web-app "Photo-Graph," (http://gendron-lab.shinyapps.io/PhotoGraph) featuring new visualizations of this mRNA-sRNA co-sequencing dataset. In summary, our findings indicate that plants regulate sRNAs within a diel cycle in a photoperiodic manner and form highly-correlated pairs with mRNAs.
    DOI:  https://doi.org/10.1371/journal.pgen.1012229
  24. Front Immunol. 2026 ;17 1857099
    RNA epitranscriptomic regulation of tumor immune evasion: mechanisms, context-dependent roles, and therapeutic implications.
    Yanni Ma, Wenzhi Deng, Xiulin Jiang, Yuxing Zhu.
      Tumor immune evasion is a fundamental hallmark of cancer progression and a major barrier to effective immunotherapy. RNA epitranscriptomic modifications have emerged as a critical layer of post-transcriptional regulation that links RNA fate control with tumor immune remodeling. These reversible modifications, including m6A, m5C, ac4C, m¹A, m7G, pseudouridine, m6Am, Nm, and A-to-I RNA editing, are dynamically regulated by writers, erasers, and readers. By modulating RNA stability, splicing, nuclear export, translation efficiency, degradation, and innate immune recognition, RNA modifications reshape multiple immune-related processes in cancer. Mechanistically, they regulate tumor immune visibility by influencing antigen processing, MHC-I expression, interferon signaling, and dendritic cell-mediated cross-presentation. They also control immune checkpoint expression, particularly the PD-1/PD-L1 axis, inflammatory signaling pathways, immune-cell recruitment and exhaustion, and metabolic immunosuppression within the tumor immune microenvironment. Importantly, the functions of RNA modification regulators are highly context dependent. The same regulator may either promote immune escape or enhance antitumor immunity depending on cancer type, cellular source, target transcript, reader protein, and microenvironmental state. From a clinical perspective, RNA modification-based molecular subtypes, prognostic signatures, and risk-score models show potential for predicting patient prognosis, immune infiltration, and response to immune checkpoint blockade. In parallel, targeting RNA modification regulators, alone or in combination with immunotherapy, radiotherapy, chemotherapy, or targeted therapy, represents an emerging therapeutic strategy. However, clinical translation remains limited by insufficient specificity, tumor heterogeneity, complex crosstalk among RNA modifications, potential toxicity, and delivery barriers. Future studies integrating RNA modification mapping with single-cell, spatial, and multi-omics technologies will be essential to define cell-type-specific regulatory networks and develop precise RNA epitranscriptomic biomarkers and therapies for cancer immunotherapy.
    Keywords:  RNA epitranscriptomics; biomarkers; cancer; immune checkpoint; immunotherapy; precision medicine; tumor immune evasion; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1857099
  25. Semin Cancer Biol. 2026 Jul 22. pii: S1044-579X(26)00072-6. [Epub ahead of print]
    Interplay Between DNA and RNA Methylation Shapes Cancer Cell Plasticity.
    Guglielmo Bove, Ugo Chianese, Antonio Beato, Nunzio Del Gaudio, Rosaria Benedetti, Lucia Altucci.
      Cellular plasticity refers to the ability of healthy cells to shift between phenotypic states and modify their characteristics to maintain tissue homeostasis and integrity. In the tumor context, cancer stem cells (CSCs) exploit this flexibility to withstand stress, facilitate tumor dissemination, and evade therapeutic interventions. Epigenetic regulation, particularly DNA methylation at CpG sites, is recognized as a well-known driver of tumor plasticity by repressing differentiation programs through modulation of chromatin accessibility. More recently, RNA modifications (epitranscriptomics) have emerged as crucial post-transcriptional regulators of gene expression that shape RNA fate and function. Among these, N6-methyladenosine (m6A), 5-methylcytosine (m5C), N1-methyladenosine (m1A), and N7-methylguanosine (m7G) contribute to the regulation of cell identity by modulating stemness-differentiation balance, stress adaptation, and epithelial-to-mesenchymal transition (EMT). Notably, dysregulation of both DNA and RNA methylation signatures is frequently observed in tumors, suggesting potential functional interactions between these regulatory layers. Emerging evidence indicates that DNA CpG methylation and RNA methylation pathways may cooperate to influence stemness, survival, and EMT-associated signaling, thereby supporting CSCs' plasticity. Although the molecular mechanisms underlying this crosstalk remain incompletely understood, accumulating studies suggest that DNA and RNA methylation could converge within interconnected regulatory networks that contribute to the control of cancer cell identity. A deeper understanding of these interactions may uncover novel vulnerabilities for targeting tumor plasticity. In this review, we summarize the current knowledge on the interplay between DNA and RNA methylation in regulating tumor plasticity, highlighting emerging mechanistic insights, functional interactions, and potential implications for future epigenetic and epitranscriptomic therapeutic strategies.
    Keywords:  CpG; DNA; Interplay; RNA; m(5)C; m(6)A; methylation
    DOI:  https://doi.org/10.1016/j.semcancer.2026.07.003
  26. J Med Chem. 2026 Jul 20.
    METTL1/WDR4 Complex: A Novel Epitranscriptomic Target at the Crossroads of RNA Methylation and Drug Discovery.
    Emanuele Fabbrizi, Gebremedhin Solomon Hailu, Andrea Mancini, Antonello Mai, Francesco Fiorentino, Dante Rotili.
      METTL1, in complex with its partner protein WDR4, is the principal writer of internal and RNA-associated N7-methylguanosine (m7G), an epitranscriptomic modification that remodels translation, RNA stability, and stress-response pathways. Across diverse cancer types, including hepatocellular carcinoma, cholangiocarcinoma, lung and bladder cancer, glioma, AML, and prostate cancer, METTL1/WDR4-driven expansion of m7G-modified tRNAs and stabilization of codon-biased mRNAs amplifies oncogenic programs governing cell-cycle progression, EMT, DNA repair, and immune evasion. Context-specific roles extend to autoimmune, cardiovascular, and neurological disorders, where METTL1 regulates hypertrophy, fibrosis, angiogenesis, neurodevelopment, and inflammation. Recent advances have established METTL1 as a tractable methyltransferase target: fragment-derived SAM-pocket ligands provide optimal starting points, and recently disclosed THIQ-based inhibitors report nanomolar inhibition, robust cellular target engagement, and functional suppression of tRNA m7G in cells. These advances provide the first chemical foothold for therapeutic modulation of m7G pathways and underscore METTL1 as a promising yet complex target requiring careful biological stratification.
    Keywords:  METTL1/WDR4; RNA methylation; cancer therapeutics; epitranscriptomics; methyltransferases
    DOI:  https://doi.org/10.1021/acs.jmedchem.6c01379
  27. Am J Transl Res. 2026 ;18(6): 4632-4648
    Acupuncture-induced HSP70 upregulation in neuroprotection: mitochondrial and anti-apoptotic mechanisms.
    Hejun Wen, San Tian, Xiao Han, Qiuyu Xiao, Hong Zhang.
      Heat shock protein 70 (HSP70) represents a major stress-inducible chaperone, holding considerable significance in regulating the proteostasis, mitochondrial homeostasis, and apoptosis in the injured nervous system. Acupuncture has shown neuroprotective effects in multiple models of neurological diseases, yet the role of HSP70 as a mechanistic link between acupuncture stimulation and neuronal protection has not been systematically clarified. To this end, current evidence on acupuncture-induced HSP70 regulation is hereby summarized, and its potential contribution to neuroprotection is accordingly discussed, with particular emphasis on mitochondrial preservation and anti-apoptotic signaling. Available studies suggest that acupuncture-associated HSP70 upregulation is linked to enhanced cellular stress adaptation, reduced oxidative injury, stabilization of Bcl-2 family-dependent mitochondrial integrity, inhibition of cytochrome c release and apoptosome formation, and suppression of downstream caspase activation. In addition to these intracellular effects, emerging evidence also uncovers the involvement of HSP70 in neuroinflammatory regulation and neuron-glia communication, suggesting its broader role in shaping the injured neural microenvironment. However, current evidence remains largely associative, leaving several key issues unresolved, including questions of causal necessity, cell-specific regulation, intercellular trafficking, and neuroimmune integration. Overall, HSP70 may represent a promising integrative mediator of acupuncture-induced neuroprotection, yet its precise mechanistic function still warrants further experimental validation.
    Keywords:  Heat shock protein 70; acupuncture; apoptosis; mitochondria; neuroinflammation; neuroprotection
    DOI:  https://doi.org/10.62347/EOUP1787
  28. Front Plant Sci. 2026 ;17 1880044
    Post-transcriptional regulation of light-stress responses and predictive modeling in vegetable Solanaceae Crops.
    Lidiia Samarina, Farida Kozhakhmetova, Arysgul Turbekova, Serik Jantassov, Yerzhan Syrgaliyev, Amangeldy Taukenov, Valery Stolyarov, Halil Demir.
      Vegetable Solanaceae crops-tomato, pepper, eggplant, and potato-are increasingly cultivated in controlled environments where light is managed both as an energy source and as a developmental and stress-regulatory signal. Programmable spectra, photoperiods, and intensities interact with heat, drought, salinity, chilling, and nutrient limitation, generating complex physiological responses that cannot be explained by transcriptional regulation alone. This review highlights post-transcriptional RNA regulation as a key interface linking light perception with stress adaptation in vegetable Solanaceae. We focus on four regulatory layers-alternative splicing, RNA stability and decay, small RNAs pathways, and translational control-that determine which transcripts are processed, stabilized, degraded, or translated under specific environmental histories. Evidence from tomato, pepper, and potato indicates that RNA-level regulation contributes to stress responses, developmental flexibility, and genotype-specific acclimation. However, direct mechanistic links between defined photoreceptor pathways and specific post-transcriptional processes remain limited in Solanaceae; therefore, mechanisms established in Arabidopsis and other model plants are treated here as testable hypotheses rather than confirmed crop mechanisms. We further discuss how machine learning can integrate multi-omics and environmental datasets to identify predictive regulatory modules connecting light regimes with stress resilience and crop performance. Progress in this field will depend on experiments that combine precise light and microclimate monitoring with isoform-resolved transcriptomics, small RNAs/degradome analyses, RNA stability measurements, and translatome profiling. Such integration can transform controlled-environment Solanaceae research from descriptive stress omics to predictive, mechanism-based crop management.
    Keywords:  Solanaceae; abiotic stress; alternative splicing; light signaling; machine learning; small RNAs; translational control
    DOI:  https://doi.org/10.3389/fpls.2026.1880044
  29. Annu Rev Genet. 2026 Jul 20.
    Organization of Ribosomal RNA Genes in Eukaryotes.
    Austen R D Ganley, Sylvie Hermann-Le Denmat.
      In eukaryotes, ribosomal RNA genes (rDNA) encode the major ribosomal RNA molecules and are typically organized into a distinctive genomic structure involving tandem repetition of a polycistronic coding region. Here, we review eukaryotic rDNA organization, emphasizing the extensive, but not absolute, conservation of the canonical organization across eukaryotes. We describe exceptions to both the canonical gene structure and tandem organization and discuss important questions and hypotheses raised by this conserved organization, which is also tolerant of alternatives. Furthermore, we examine variations in rDNA copy/array number and their implications, including whether variants are likely to be adaptive, a passive consequence of ongoing cellular processes, or the outcome of interrepeat competition within rDNA arrays. Finally, we describe how recent technological advances offer great promise for overcoming the barriers imposed by the repetitive nature of rDNA and thus for improving our understanding of this fascinating region of the genome.
    DOI:  https://doi.org/10.1146/annurev-genet-011626-023157
  30. Ageing Res Rev. 2026 Jul 19. pii: S1568-1637(26)00257-6. [Epub ahead of print]121 103265
    Phytochemicals modulating HSF-1-associated pathways: A systematic review of longevity-extending mechanisms in Caenorhabditis elegans.
    Kaiming Ren, Duo Lu, Lin Wang, Jun Yang, Honglei Zhang.
      Aging is characterized by progressive loss of proteostasis, and heat shock transcription factor 1 (HSF1) is the master regulator of the cellular stress response, making it an attractive pharmacological target for interventions aimed at extending lifespan. However, a systematic synthesis of phytochemicals that modulate HSF1 has been lacking. Following PRISMA 2020 guidelines, we systematically searched PubMed, Web of Science, Scopus, Embase, and the Cochrane Library from March 2016 to March 2026, identifying 42 original studies that provided clear evidence of HSF-1 activation (nuclear translocation, phosphorylation, or transcriptional activity), together with downstream stress-response markers such as upregulation of heat shock protein genes by phytochemicals with lifespan-extending or health span-improving outcomes. All 42 studies exclusively used Caenorhabditis elegans as the model organism, and the phytochemicals were classified into six categories: plant extracts/mixtures (11 studies), flavonoids (9 studies), carbohydrates/sugars (8 studies), terpenoids (7 studies), phenolic compounds (4 studies), and alkaloids (3 studies). Across all studies, these phytochemicals extended lifespan, enhanced resistance to thermal and oxidative stress, and delayed neurodegenerative pathology (Alzheimer's, Parkinson's, and Huntington's disease models) through activation of HSF-1 and its cooperating transcription factors DAF-16/FOXO and SKN-1/Nrf2. While sharing a common dependency on HSF-1, different classes engaged additional signaling pathways including autophagy, mitochondrial unfolded protein response, insulin/IGF-1 signaling, and lipid metabolism, reflecting class-specific mechanistic signatures. This systematic review provides the first comprehensive evidence base for developing HSF-1-associated longevity strategies using phytochemicals; however, all available evidence is limited to C. elegans models, and urgent validation in mammals and clinical translation are needed before these findings can be applied to human aging.
    Keywords:  Aging; Caenorhabditis elegans; HSF-1; Health span; Heat shock transcription factor 1; Lifespan; Phytochemicals; Systematic review
    DOI:  https://doi.org/10.1016/j.arr.2026.103265
  31. Front Cell Dev Biol. 2026 ;14 1864321
    m6A RNA modification: a central epitranscriptomic switch orchestrating oncogenic signaling and glycolytic reprogramming in cancer.
    Yonggang Guo, Ruilong Kou, Zhizhong Huang, Zhihua Chen, Heng Yun.
      N6-methyladenosine (m6A) is the most widespread, abundant, and conserved post-transcriptional modification in eukaryotic RNA, and it participates in the regulation of various biological processes, especially playing a crucial role in tumorigenesis and progression. During tumor progression, abnormal expression of m6A regulatory proteins often leads to dysregulation of m6A modification levels, thereby affecting tumor pathophysiology. Recent studies have shown that in various tumor types, m6A modifications on target mRNAs and non-coding RNA transcripts can regulate the activity of various oncogenic signaling pathways; moreover, m6A modifications can also regulate the tumor glycolysis process through multiple molecular mechanisms, thereby affecting the proliferation, invasion, and metastasis of tumor cells and other biological behaviors. Most existing reviews focus only on the unidirectional regulatory relationships among m6A modification, oncogenic signaling, and glycolysis, while overlooking the crosstalk among the three. To address this gap, this review systematically summarizes the regulatory effects of m6A modifications on key glycolytic enzymes and various cancer signaling pathways, examines in depth the molecular mechanisms by which the three cooperatively participate in tumorigenesis and progression, comprehensively dissects the bidirectional crosstalk among the three core functional modules within this network, and further proposes a self-stabilizing "m6A-signaling-glycolysis closed-loop regulatory network," and provides future research directions for this field. It offers theoretical references for related basic research and clinical diagnosis and treatment.
    Keywords:  M6A; epitranscriptomics; glycolysis; signaling pathway; tumor
    DOI:  https://doi.org/10.3389/fcell.2026.1864321
  32. Physiology (Bethesda). 2026 Jul 18.
    Dietary modulation of CMA: implications for cancer prevention and therapy.
    Cecilia Sanchez-Felipe, Esperanza Arias, Julio Madrigal-Matute.
      Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway that links nutrient availability to intracellular proteostasis through the targeted turnover of selective cytosolic proteins. Through this selective control of protein quality, CMA participates in the regulation of metabolic adaptation, cellular homeostasis, and stress responses. CMA is highly responsive to nutritional cues, including caloric restriction (CR), fasting, and changes in macronutrient composition, positioning this pathway as a key mediator of cellular adaptation to metabolic stress. In cancer, CMA displays context-dependent functions that influence tumor metabolism, genomic stability, and survival under adverse microenvironmental conditions. These dual roles suggest that dietary modulation of CMA may shape tumor initiation and progression through effects on cellular proteostasis and metabolic plasticity. In this review, we summarize current knowledge on the molecular mechanisms by which nutritional signals regulate CMA and discuss the physiological implications of nutrition-driven CMA modulation for cancer prevention and therapy.
    DOI:  https://doi.org/10.1152/physiol.00014.2026
  33. Cell Signal. 2026 Jul 24. pii: S0898-6568(26)00420-1. [Epub ahead of print] 112763
    Impaired mitochondrial quality control and stress signalling machinery modulate senescence induction by genotoxic challenge.
    Mia Simons Weston, Marta Dominguez Prieto, Nicoleta Moisoi.
      Cellular senescence is a hallmark of ageing and age-related disease and is closely associated with mitochondrial dysfunction and the accumulation of DNA damage. However, the contribution of mitochondria-nucleus communication, mitochondrial quality control (mtQC) and stress signalling to senescence remains incompletely understood. Here, we investigated the interplay between mtQC pathways and cellular stress responses in DNA damage-induced senescence using mouse embryonic fibroblasts (MEFs). MEFs deficient in the mitochondrial protease HtrA2 (proteostasis), the transcription factor Chop (integrated stress response; ISR) or the mitophagy regulator Pink1 were exposed to three mechanistically distinct DNA-damaging agents: bleomycin, etoposide and doxorubicin. Senescence was characterised using multiple complementary markers, including the proportion of high senescence-associated β-galactosidase-positive cells, nuclear size, total and nuclear p21 abundance, and transcriptional analysis of p16, p21 and genes associated with cell-cycle regulation and stress signalling. Mitochondrial dysfunction through mtQC impairment enhanced sensitivity to senescence with HtrA2 and Pink1 loss promoting increased senescence under DNA damage. Although DNA damage response (DDR) was activated as seen by changes in p21 homeostasis, this did not always correlate with senescence levels, which indicates that DDR alone cannot account for all senescence characteristics. The ISR played a modulatory role in the senescence induction, with Chop loss of function reducing senescence induction following DNA damage despite DDR activation. The different DNA damaging drugs produced different senescence outcomes, thus highlighting the importance of the stressor context in addition to the cellular homeostasis mechanisms in the overall senescence profile. This approach allowed, for the first time, to identify senescence subtypes dependent of mtQC and ISR integrity in the context of genotoxic stress.
    Keywords:  Genotoxic stress; Integrated stress response; Mitochondria quality control; Senescence subtypes
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112763
  34. Front Immunol. 2026 ;17 1888266
    G3BP1 methylation by PRMT5 facilitates its recruitment of TBK1 for IRF3 activation during host response to foreign ribonucleic acids.
    Wen Song, Susana Soo-Yeon Kim, Candice Yam, Joey Teo, Jyue Yuan Lim, Xuezhi Bi, Hong-Hwa Lim, Kong-Peng Lam.
       Background and aim: Ras GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) has been shown to bind cytosolic nucleic acid sensors including retinoic acid-inducible gene I (RIG-I) and cyclic GMP-AMP synthase (cGAS) in innate immunity. As a scaffolding protein enhancing protein-protein and protein-RNA interactions during cellular stress response, we examine whether G3BP1 could bind additional innate immune signaling molecules and investigate the relevance and mechanisms underlying these interactions.
    Methods: To define G3BP1 function in dsRNA-triggered anti-viral signaling and identify additional interacting molecules, we generated siRNA- and CRISPER-Cas9-mediated G3BP1-knockdown and knockout HEK293T cells, conducted biochemical experiments in human and murine cells including co-immunoprecipitation, domain mutagenesis and mapping, as well as LC-MS/MS analyses to study protein post-translational modifications. We also performed p(I:C)-stimulation assays to measure interferon production, pharmacological inhibition studies to determine enzyme-substrate specificity, as well as confocal immunofluorescence microscopy to examine protein subcellular localization.
    Results: Our study reveals a role for G3BP1 in binding TBK1 and IRF3, two important molecules in innate immune signaling leading to the production of IFN-β. Deficiency in G3BP1 reduces TBK1-IRF3 complex formation and affects IRF3 phosphorylation, nuclear translocation, and the production of IFN-β during p(I:C) stimulation while the phosphorylation of TBK1 was largely preserved. We further show that G3BP1 constitutively associates with IRF3 and recruits TBK1 upon p(I:C) stimulation. These findings suggest that G3BP1 acts as a scaffold to recruit activated TBK1 and facilitates its activation of IRF3. Domain mapping experiments indicated that the C-terminal RGG region of G3BP1 is critical for binding IRF3 and TBK1. LC-MS/MS analysis revealed human G3BP1 to be arginine-methylated at R435 and R460 residues upon p(I:C)-stimulation, and mutagenesis experiments indicated that R460 is required for its efficient binding of TBK1. We further show that the arginine methyltransferase PRMT5 associates with and promotes the symmetric arginine-dimethylation of G3BP1 and pharmacological inhibition of PRMT5 impaired G3BP1-TBK1 interaction.
    Conclusions: Together, our data indicate that G3BP1 could bind PRMT5, TBK1 and IRF3 and reveal G3BP1 as a signaling hub that constitutively binds IRF3 and is arginine-methylated by PRMT5 to recruit TBK1 for IRF3 phosphorylation and activation and the induction of interferon production during host antiviral response.
    Keywords:  G3BP1; RNA-sensing; adaptor protein; innate immunity; interferon
    DOI:  https://doi.org/10.3389/fimmu.2026.1888266
  35. Appl Environ Microbiol. 2026 Jul 20. e0074726
    A haloarchaeal VapBC toxin-antitoxin system: regulatory mechanism and role in establishing population heterogeneity to facilitate survival of subpopulations under stress conditions.
    Dan He, Yuqi Lin, Yanyan Zhang, Yang Liu, Ping Li, Xin Su, Xiaoyi Qu, Yaru Liu, Xianyi Shao, Hongbo Wen, Hongyi Luo, Yi Wu, Fei Gan, Xiao-Feng Tang, Bing Tang.
      Toxin-antitoxin (TA) systems are ubiquitously distributed in bacteria and archaea and have been implicated in various functions such as plasmid maintenance, phage defense, biofilm formation, stress response, and persistence, but their regulatory mechanisms and roles in haloarchaea are largely unknown. In this study, we found that four of the eight putative VapBC TA systems of Natrinema gari J7-2 are functional in strain J7-2 and Haloferax volcanii. Among them, the NgVapBC1 system is composed of the antitoxin NgVapB1 and the toxin NgVapC1, and the two proteins could form a NgVapBC1 complex. The NgVapBC1 system could be transcriptionally autoregulated, wherein a pseudo-palindromic sequence in the vapBC1 operon promoter acts as a negative cis-regulatory element, and the NgVapBC1 complex is a stronger repressor than NgVapB1. The qRT-PCR and in vivo toxicity analyses showed that strain J7-2 maintains a high vapB1/vapC1 mRNA ratio through truncation of the vapBC1 operon transcript within the toxin-coding region for preventing the synthesis of excess toxin NgVapC1 to release toxicity abnormally. Mutational analyses showed that differential start codon usage by vapB1 and vapC1 and a -4 nt overlap of their stop and start codons contribute to maintaining a higher vapB1/vapC1 mRNA ratio, and the -4 nt overlap-mediated translational coupling of vapB1 and vapC1 would enable both post-transcriptional and translational regulation of the NgVapBC1 system. The phenotypic comparison of strain J7-2 and its ΔvapBC1 mutant revealed that the NgVapBC1 system contributes to population heterogeneity of decline-phase rather than exponential-phase strain J7-2 and facilitates the survival of subpopulations under stress conditions.IMPORTANCEAlthough TA systems are regarded as versatile modulators of prokaryotic cell fate, their bona fide physiological roles remain elusive. Moreover, so far, there is no report on the regulatory mechanism and function of haloarchaeal VapBCs, which constitute the major group of TA systems in haloarchaea. Our results demonstrate that a VapBC system of the haloarchaeon Natrinema gari J7-2 is regulated at multiple levels and mediates the establishment of population heterogeneity, thereby facilitating the survival of the strain J7-2 population as a whole in diverse and changing environments. This study provides the first experimental evidence of the regulatory mechanism of the biological role of the VapBC system in conferring fitness advantages to haloarchaea.
    Keywords:  VapBC; haloarchaea; regulation; stress resistance; toxin-antitoxin system
    DOI:  https://doi.org/10.1128/aem.00747-26
  36. Chem Biol Interact. 2026 Jul 18. pii: S0009-2797(26)00368-6. [Epub ahead of print]437 112260
    ER stress-dependent Ddit4/REDD1 induction contributes to translational suppression during cisplatin-induced skeletal muscle atrophy.
    Hayato Nanri, Hiroyasu Sakai, Kaisei Umeyama, Takayuki Ogiwara, Shinki Soga, Yuya Chigusa, Shiori Yonamine, Risako Kon, Nobutomo Ikarashi, Yoshihiko Chiba, Kumiko Ogawa.
      Cisplatin is a widely used chemotherapeutic agent whose clinical utility is limited by various adverse effects. Although skeletal muscle loss during chemotherapy is often attributed to cachexia or generalized wasting, accumulating evidence indicates that cisplatin directly induces skeletal muscle atrophy. However, the underlying cellular stress responses and signaling pathways remain unclear. In this study, we investigated the involvement of endoplasmic reticulum (ER) stress and translational regulation in cisplatin-induced skeletal muscle atrophy, focusing on DNA damage-inducible transcript 4/Regulated in development and DNA damage response-1 (Ddit4/REDD1), a stress-responsive inhibitor of mammalian target of rapamycin complex 1 (mTORC1). Using a mouse model and differentiated C2C12 myotubes, we examined ER stress signaling, protein synthesis, and mTORC1 activity following cisplatin treatment, and evaluated the effects of tauroursodeoxycholic acid (TUDCA), an ER stress-suppressing chemical chaperone. Cisplatin induced skeletal muscle atrophy accompanied by ER stress activation and suppression of protein synthesis in mice. TUDCA significantly attenuated muscle mass and strength loss without affecting body weight reduction. Cisplatin upregulated ER stress-responsive genes and decreased phosphorylation of p70 S6 kinase, whereas these changes were suppressed by TUDCA. Pharmacological ER stress induction increased Ddit4/REDD1 expression, and PERK inhibition reduced cisplatin-induced Ddit4/REDD1 upregulation in C2C12 myotubes. Furthermore, Ddit4/REDD1 knockdown partially restored protein synthesis and mTORC1 signaling. These findings indicate that cisplatin induces skeletal muscle atrophy via ER stress-associated translational suppression, at least partly through Ddit4/REDD1-mediated inhibition of mTORC1.
    Keywords:  Cisplatin; Ddit4/REDD1; ER stress; Muscle atrophy; mTORC1
    DOI:  https://doi.org/10.1016/j.cbi.2026.112260
  37. Hum Mol Genet. 2026 Jul 15. pii: ddag066. [Epub ahead of print]35(15):
    DDX3X syndrome mutations lock DDX3X-RNA conformational states to drive persistent pathological condensation and neuronal death.
    Poulami Ghosh, Shivani Krishna Kapuganti, Sabhyata Gopal, Vhasnsciani A R, Swati Lamba, Purusharth I Rajyaguru, Sannula Kesavardhana.
      DDX3X is a highly conserved RNA helicase associated with RNA metabolism, translation initiation, and deciding cell fate choices. Spontaneous mutations in DDX3X cause a rare genetic human disorder called DDX3X syndrome, showing a spectrum of neurodevelopmental and intellectual abnormalities. How missense mutations in DDX3X lead to aberrant cellular functions and pathological consequences is unclear. Here, we demonstrate that specific DDX3X syndrome missense mutations induce the formation of persistent, solid-like DDX3X stress granules by structurally altering the conformation of the DDX3X-RNA complex. Structural interrogation of DDX3X syndrome missense mutations revealed critical mutations that perturb the DDX3X-RNA complex, exhibit high clinical pathogenicity scores, and are associated with cancers. N and C-terminal mutations adjacent to the helicase domain of the DDX3X (F182V, I190S, T198P, L556S, and L559H) showed augmented stress granule (SG) assembly, and formation of persistent DDX3X-SGs in neuronal and non-neuronal cells. Intriguingly, these mutations altered the liquid-like properties of DDX3X-SGs, forming solid-like SGs. Mechanistically, these mutations drive the persistent DDX3X-SGs by either locking DDX3X in an open, RNA-bound conformation or by increasing the rigidity of the DDX3X-RNA complex (I190S; T198P), thereby conferring a loss of liquid-like properties. The persistent solid-like DDX3X-SGs preferentially promoted neuronal lytic cell death and did not affect translation. Also, the C-terminal L556S and L559H mutations, which form persistent granules, promoted the DDX3X-driven β-amyloid aggregation. Our observations indicate that DDX3X syndrome mutations near the N- and C-termini promote the formation of solid-like DDX3X condensates, neuropathological aggregation, and neuronal cell death, which might underlie the disease pathogenesis in humans.
    Keywords:  Cell signaling; Developmental disorders; Genetic disease; Neurodegeneration; Rare disease; Structural variant
    DOI:  https://doi.org/10.1093/hmg/ddag066
  38. Cell Host Microbe. 2026 Jul 22. pii: S1931-3128(26)00279-9. [Epub ahead of print]
    RNA quality control enables antibiotic tolerance.
    Andrew T Nishimoto, Juan C Ortiz-Marquez, Michelle R Scribner, Yanying Yu, Qidong Jia, Haley Echlin, Amy R Iverson, Abigail E McKnight, Nadia Olivero, Aaron Poole, Enolia Marr, Jordan Coggins, Adam Rosenthal, Chrispin Chaguza, Randolph K Larsen, Mark E Hatley, Ralph R Isberg, Vaughn S Cooper, Tim van Opijnen, Jason W Rosch.
      Antibiotic resistance poses significant challenges, yet pathogen adaptation pathways vary. To determine how host environments affect adaptation, we experimentally evolved Streptococcus pneumoniae in mice subjected to antibiotics in the context of distinct immune states. High fitness costs of canonical resistance restrict its emergence. Instead, populations adopt context-specific adaptive strategies. While neutrophil-replete environments select for immune-evasive mutations in nicotinamidase, general antibiotic stress drives convergent mutations in rny, encoding the RNA degradosome scaffold RNase Y. In contrast, antibiotic-induced death in wild-type bacteria is driven by transcriptional collapse; rny mutants avert this fate via a bet-hedging strategy, in which a resilient minority maintains a near-baseline transcriptional profile while a majority undergoes selective RNA degradation to preserve transcript fidelity. Upon stress removal, these populations execute a prioritized transcriptional ribosomal reboot, facilitating recovery. Thus, RNA turnover is a tunable master regulator of stress tolerance that pathogens exploit to survive the combined pressures of antibiotics and immunity.
    Keywords:  RNA degradosome; RNase Y; Streptococcus pneumoniae; antibiotic resistance; antibiotic tolerance; antibiotic treatment failure; enabler; immune state; in vivo evolution; mutations
    DOI:  https://doi.org/10.1016/j.chom.2026.06.019
  39. G3 (Bethesda). 2026 Jul 21. pii: jkag172. [Epub ahead of print]
    Proteome analyses reveal endoplasmic reticulum stress-induced changes in protein abundance associated with Ube2j2 deficiency in human cell culture.
    Caroline L Dahlberg, Matthew Zinkgraf, Sophie Heiden Laugesen, Cecile Lützen Søltoft, Queralt Ginebra, Eric Paul Bennett, Rasmus Hartmann-Petersen, Lars Ellgaard.
      The unfolded protein response (UPR) helps reinstate cellular proteostasis upon an accumulation of misfolded proteins in the endoplasmic reticulum (ER), in part through ER-associated degradation (ERAD). Ube2j2 is an ER-localized E2 ubiquitin-conjugating enzyme that participates in ERAD. We used mass spectrometry analysis of cultured U2OS cells to investigate how the loss of Ube2j2 affects the cellular proteome in response to tunicamycin-induced ER stress. We constructed a network of twelve statistically distinct modules of protein abundance profiles across conditions. We describe the gene ontology annotations for each module along with the "hub gene" proteins whose abundance levels most closely adhere to each module's protein abundance profile. Our analysis identifies known Ube2j2-associated pathways (eg the UPR and ERAD) and cellular functions that were previously unassociated with Ube2j2 (eg RNA metabolism, ER-Golgi transport, and cell-cycle progression). These data are available via ProteomeXchange with identifier PXD076153 and provide avenues for further investigation into the cellular functions of Ube2j2 under basal and ER-stressed conditions.
    Keywords:  E2 ubiquitin-conjugating enzyme; ER-associated degradation; Ube2j2; protein degradation; proteomics; ubiquitin proteasome system; unfolded protein response
    DOI:  https://doi.org/10.1093/g3journal/jkag172
  40. J Neurochem. 2026 Jul;170(7): e70528
    Is Nuclear mTOR Relevant for Neuronal Dysfunction?
    Shiwani Kumari, Roberto Pagano, Katarzyna Orzol, Jacek Jaworski.
      The mammalian target of rapamycin (mTOR) is a key regulator of neuronal development, metabolism, and plasticity, and its dysregulation is linked to many neurological disorders. Most studies have focused on cytoplasmic mTOR, yet mTOR is also present in the nucleus. In non-neuronal cells, nuclear mTOR has been linked to transcription, chromatin organization, and RNA metabolism. In neurons, its role remains largely unknown. Here, we present a focused Perspective on nuclear mTOR in the nervous system. We briefly summarize the best-established nuclear functions of mTOR, drawing mainly on evidence from non-neuronal cells. We then reanalyze published mTOR interactome datasets to assess whether these mechanisms may be relevant to neurons. Repeated links were observed to nuclear processes, particularly transcription, chromatin regulation, RNA processing, and DNA repair. Similar patterns were observed for gene sets associated with neurodevelopmental and neurodegenerative disorders. However, these associations are correlative and do not establish causality. Based on these findings, we propose a set of testable predictions and experimental approaches to directly examine nuclear mTOR function in neurons, including selective perturbation of its nuclear activity and analysis of gene expression and RNA processing. A key open question is whether nuclear mTOR has a functional role in neurons beyond its well-established cytoplasmic activities. This Perspective summarizes current evidence, highlights key gaps, and outlines directions for future studies on nuclear mTOR in neuronal function and disease.
    Keywords:  gene expression regulation; mTOR signaling; neuronal dysfunction; neuronal physiology; nuclear mTOR
    DOI:  https://doi.org/10.1111/jnc.70528
  41. Plant Cell Rep. 2026 Jul 24. pii: 233. [Epub ahead of print]45(8):
    Phosphorylation networks as regulatory hubs in plant stress signaling: kinase dynamics, crosstalk, and network plasticity.
    Teja Manda, Delight Hwarari, Raphael Dzinyela.
      Agriculture faces significant limitations from climate change, soil degradation, and a wide range of abiotic and biotic stresses that continually threaten global food security. Although transcriptional and hormonal regulatory networks have been extensively studied, post-translational modifications (PTMs), particularly phosphorylation, remain comparatively underexplored despite their central role in rapid stress signaling. In this review, we synthesize recent advances in phosphoproteomics, kinase network mapping, and systems biology to highlight phosphorylation as a key regulatory hub in plant stress responses. Drawing from both model species and crops, we emphasize major kinase families, including MAPKs, CDPKs, RLKs, and SnRK1/TOR, which translate calcium signatures, reactive oxygen species (ROS) waves, and cellular energy status into precise physiological outputs. We also discuss how multi-omics integration, precision breeding, synthetic biology, and microbiome engineering can leverage phosphorylation dynamics to advance climate-smart agriculture. By outlining phosphorylation networks as functional regulators, this work underscores their translational potential for developing resilient crops that can maintain yield under environmental extremes.
    Keywords:  Phosphoproteomics; Phosphorylation; Post-translational modification; Protein kinases; Stress signaling
    DOI:  https://doi.org/10.1007/s00299-026-03917-3
  42. Microb Cell Fact. 2026 Jul 20.
    Transcriptional reprogramming of the stress response and translational-secretory machinery enhances recombinant secreted protein production in Yarrowia lipolytica.
    Maria Gorczyca, Piotr Kubiak, Ewelina Celińska.
      Protein synthesis and secretion processes are non-pathway traits. The genetic complexity makes them very challenging to engineer and genetically optimize. Therefore, we exploit transcriptional reprogramming to create a favorable cellular environment for a trait of interest. In this study, we investigate the effects of transcription factor (TF) engineering on secretory recombinant protein (rProt) production in Y. lipolytica. High-throughput genome-wide pre-screening guided the TFs selection. Here, we run high-throughput functional studies, followed by transcriptome analysis for selected TF-modified strains from semi-steady state. We contrasted the overexpression (OE) vs. deletion (KO) genotypes for their capacity to produce two reporter proteins (fluorescent model and glucoamylase). Despite a wide set of TF-modified strains analyzed here, only several displayed consistent, unbiased phenotypes. Collected data indicated that the known general stress response TFs, Msn4 and Hsf1, elicit their highly beneficial rProt-promoting function specifically towards a "challenging" rProt, while the levels of "simple" rProt remain unaffected. Deletion of the previously identified strong repressor of intracellular rProt synthesis, Azf1, significantly enhanced production of secretory rProt. At the transcriptomic level, deletion of Azf1 was associated with massive upregulation of ribosome biogenesis and cytoplasmic translation, which underwent alternative splicing (global differential exon usage analysis). The results of contrasting the Azf1- and Dep1-driven regulomes (the latter identified as a strong repressor of intracellular rProt synthesis, with no positive effect on the secretory rProt production) suggest that for efficient rProt secretion, upregulation in the vesicle-mediated transportation must co-occur, as in the case of Azf1-KO. In our experimental setting, OE of the general stress response TFs was beneficial for the production of "problematic", UPR-awakening rProt, and deletion of Azf1 for tuning a molecular background beneficial for secretory rProt.
    Keywords:  Global transcription reprogramming; Recombinant protein synthesis; Ribosomal-translational capacity; Transcription factor; Yeast
    DOI:  https://doi.org/10.1186/s12934-026-03062-2
  43. Front Cell Dev Biol. 2026 ;14 1895114
    RNA modifications in radiotherapy resistance and radiosensitization: epitranscriptomic regulation of tumor response to radiation.
    Hongran Qin, Shuqiang Yang, Jiawei He, Meijia Zhao, Luqian Zhao, Jingjing Wang, Xiulin Jiang, Xin Xu, Xiaowen Chen.
      Radiotherapy (RT) remains a major treatment for solid tumors, but durable tumor control is frequently limited by adaptive DNA repair, altered cell-death thresholds, cancer stemness, metabolic plasticity, and immune escape. RNA modifications have recently emerged as rapid post-transcriptional regulators that enable tumor, stromal, and immune cells to remodel these programs after irradiation. This Mini Review emphasizes three major themes. First, N6-methyladenosine (m6A) is the best-characterized RNA modification in RT response, with METTL3/METTL14, FTO, ALKBH5, YTH-domain readers, and IGF2BP proteins regulating DNA repair, apoptosis, ferroptosis, stemness, metabolism, and immune checkpoints in a highly context-dependent manner. Second, non-m6A modifications, including 5-methylcytosine (m5C), N4-acetylcytidine (ac4C), 7-methylguanosine (m7G), and A-to-I RNA editing, are increasingly linked to homologous recombination, metabolic adaptation, innate immune sensing, and immune evasion, although their RT-specific evidence remains limited and should be viewed as emerging rather than established. Third, therapeutic targeting of RNA-modifying enzymes may improve radiosensitization only when guided by tumor type, cellular context, RT dose and fractionation schedule, predictive biomarkers, and normal-tissue safety. Accordingly, we organize current evidence around RNA-modification machinery, tumor-intrinsic mechanisms of radioresistance, immune microenvironment remodeling, and barriers to clinical translation. We further highlight the need to move beyond single-axis models toward dynamic, spatial, and clinically validated analyses of RNA modification networks during fractionated RT.
    Keywords:  DNA damage repair; RNA modifications; epitranscriptomics; ferroptosis; radioresistance; radiosensitization; radiotherapy; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2026.1895114
  44. BMC Bioinformatics. 2026 Jul 18.
    DB-IRES: a deep learning model based on ensemble learning for predicting internal ribosome entry sites.
    Pengxuan Song, Mingwei Sun, Jianhua Jia.
       BACKGROUND: Internal ribosome entry sites (IRES) are cap-independent translation initiation elements present in specific viral and cellular mRNAs. They facilitate direct ribosome recruitment for protein synthesis, bypassing the need for the canonical 5' cap structure. Due to their pivotal roles in viral pathogenesis and cellular translational regulation, precise identification of IRES is crucial for advancing mechanistic studies and exploring potential therapeutic interventions. Nonetheless, manual identification is both labor-intensive and costly, while current computational methods exhibit limitations in accuracy and robustness.
    RESULTS: DB-IRES is a novel deep learning model designed for this purpose, incorporating densely connected 1D convolutional neural network blocks, bi-directional gated recurrent units, and a self-attention mechanism within an ensemble learning framework. Trained with a five-fold cross-validation strategy, the final integrated model exhibits superior and more robust predictive performance compared to existing methods on an independent test set. The model consistently achieves enhanced discriminatory capabilities across multiple evaluation metrics, thereby validating the effectiveness of its hybrid architecture and ensemble design.
    CONCLUSIONS: DB-IRES serves as a reliable and precise computational tool for predicting IRES elements. Its improved performance enables more in-depth functional investigations of IRES biology and supports wider applications in RNA research and the development of associated therapeutics.
    Keywords:  Bagging; Cap-independent translation; Deep learning; DenseNet; Ensemble learning; IRES
    DOI:  https://doi.org/10.1186/s12859-026-06551-8
  45. Biochemistry. 2026 Jul 23.
    Conformational and Functional Divergence of RnpA Protein Subfamilies in Bacterial Ribonucleoprotein RNase P.
    Loc Huynh, Reza Esmaeeli, Tingyi Zhu, Swapnil Joshi, Krushna Mishra, Robin Fournier, Alberto Perez, Michael E Harris.
      Bacterial ribonuclease P (RNase P) is an essential ribonucleoprotein enzyme that catalyzes 5' leader removal from precursor tRNAs (ptRNAs) using a catalytic RNA subunit (P RNA) and an essential protein cofactor (RnpA). RnpA binds near the P RNA active site, facilitating catalysis and enhancing ptRNA binding by contacting 5' leader sequences. However, key information regarding how sequence variation, particularly among bacterial pathogens, influences folding, dynamics, P RNA activation, and catalytic function is lacking. Using sequence similarity network (SSN) analyses of >1800 RnpA sequences, we identify two major subfamilies, a Bacilli-specific class (RnpA-1) that associates with divergent Type B P RNAs, and a broader class (RnpA-2) that associates with ancestral Type A P RNAs, with species-specific variation concentrated at the N- and C-termini. Computational and biophysical studies show that RnpA-1 proteins, including those from Staphylococcus aureus and Enterococcus faecium, exhibit greater conformational dynamics and reduced thermal stability relative to RnpA-2 proteins from representative Gram-negative pathogens. Despite these differences, both families comparably enhance binding of ptRNA to their cognate Type A or B P RNA. In contrast, kinetic studies reveal higher kcat values for Type B RNase Ps and rate limiting product release, while Type A enzymes are limited by precatalytic steps. Reconstitution with noncognate subunits produces selective defects in either kcat or KM demonstrating that RnpA identity makes distinct contributions to substrate binding and catalytic activation. These results further define the conserved and divergent structural, dynamic and functional features of RnpA proteins and establish a foundation for understanding biological function and inhibitor targeting.
    DOI:  https://doi.org/10.1021/acs.biochem.6c00277
  46. Oncol Lett. 2026 Sep;32(3): 396
    FUBP3 regulates expression and alternative splicing of genes associated with cell proliferation and apoptosis in cancer cells.
    Lingyu Kong, Chaoxu Fu, Xuesong Li, Mingxin Chen, Xinqi Liu, Min Zhou, Tongshu Wang, Hongxin Piao.
      Far upstream element binding protein (FUBP)3, a member of the FUBP family of proteins, is a DNA-binding transcription activator and an RNA-binding protein. FUBP3 is deregulated in various types of human cancer and promotes cell proliferation. However, the underlying molecular mechanism of FUBP3 in cancer is still unclear. Therefore, the present study investigated the cell biology, gene expression profile and alternative splicing pattern of HeLa and Huh7 cells following FUBP3 knockdown, in comparison with control cells. The results showed that FUBP3 knockdown promoted proliferation and inhibited apoptosis of HeLa cells, but inhibited the proliferation of Huh7 cells. FUBP3 knockdown markedly affected the transcriptional level of genes involved in cell adhesion, cell proliferation and the apoptotic process. Furthermore, FUBP3 broadly regulated the alternative splicing of hundreds of genes with functions in cellular component disassembly and the apoptotic process. Validation experiments using reverse transcription-quantitative PCR demonstrated that FUBP3 regulated the expression and alternative splicing of genes associated with cell adhesion, cell proliferation and apoptosis in the HeLa and Huh7 cells lines. These results indicated that FUBP3 could regulate the proliferation and apoptosis of cancer cells perhaps via different gene expression and splicing regulation, which thus furthers the current understanding of the role of FUBP3 in cancer.
    Keywords:  RNA-sequencing; alternative splicing; apoptosis; cell proliferation; far upstream element binding protein 3; gene expression
    DOI:  https://doi.org/10.3892/ol.2026.15751
  47. Toxicol Sci. 2026 Jul 24. pii: kfag088. [Epub ahead of print]
    Systematic comparison of temporal hepatotoxicant-induced gene network responses across three liver test systems.
    Tamara Y Danilyuk, Marou Schouten, Elsje J Burgers, Barira Islam, Joost B Beltman, Peter Bouwman, Giulia Callegaro, Bob van de Water.
      Drug-induced liver injury (DILI) arises from dynamic and time-dependent cellular stress responses that remain insufficiently captured by conventional single-timepoint toxicogenomic assessments. We systematically characterized temporal and concentration-dependent transcriptomic responses to the clinically relevant hepatotoxicants ketoconazole, diclofenac and nitrofurantoin across three human liver in vitro models: primary human hepatocytes (PHH), hiPSC-derived hepatocyte-like cells (HLC) and HepG2 cells. Time-resolved RNA sequencing (0-48 hours) combined with likelihood ratio testing identified time-responsive genes (TRGs), which were subsequently integrated into TXG-MAPr gene co-expression modules to enable mechanistic interpretation at the network level. Across all models and compounds, a conserved core stress response was observed, characterized by activation of ER stress (ATF4), oxidative stress (NRF2) and heat shock (HSF1) pathways, while distinct model-specific adaptive programs reflected differences in metabolic competence and differentiation status. Mapping TRGs onto co-expression networks revealed coordinated temporal activation patterns and highlighted both shared and system-specific transcriptional programs. Concentration-response analysis at 24 hours demonstrated that module-level transcriptomic points of departure (tPODs) were highly reproducible across models for a subset of functionally annotated networks, particularly ER stress modules associated with hepatocellular injury in vivo. Notably, these modules showed substantial gene-level concordance across systems, supporting their biological robustness and translational relevance. These findings establish that time-resolved, network-based transcriptomics provides mechanistically grounded, reproducible and quantitative endpoints that enhance cross-system comparability and offer a scalable framework for regulatory toxicology and next-generation chemical risk assessment.
    DOI:  https://doi.org/10.1093/toxsci/kfag088
  48. Geroscience. 2026 Jul 22.
    The PERK paradox in aging: how ER stress shapes senescence and neurodegeneration.
    Vivek Pandey, Rahul Sachdeva, Sanda Despa.
      Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are now recognized as integral components of the proteostasis network that preserves cellular and tissue function across the lifespan. With aging, increasing oxidative load, metabolic imbalance, and Ca2⁺ dysregulation elevate the burden of misfolded proteins in the ER, leading to progressive UPR engagement. When ER stress is mild or transient, UPR signaling restores folding capacity, restrains translation, and enhances redox and degradative programs, thereby promoting cellular resilience. In contrast, persistent or repeatedly unresolved ER stress narrows this adaptive window and biases UPR outputs toward chronic inflammation, stable growth arrest, and cell loss processes that collectively drive inflammaging, stem/progenitor exhaustion, tissue degeneration, and vulnerability to neurodegenerative disease. This review synthesizes evidence that ER stress is not merely a correlation of aging but a mechanistic contributor to age-related decline, with senescence emerging as a major downstream fate in multiple tissues. It also highlights how context- and duration-dependent PERK signaling can be protective early, yet maladaptive when chronically engaged, shaping senescence programs and influencing neuronal survival and neurodegenerative disease progressions. Finally, this review discusses therapeutic opportunities and open questions centered on restoring adaptive PERK/ISR dynamics to support healthy aging.
    Keywords:  Aging; ER stress; Neurodegeneration; Senescence; Unfolded protein response
    DOI:  https://doi.org/10.1007/s11357-026-02430-5
  49. Anim Genet. 2026 Aug;57(4): e70169
    Nuclear Stress Bodies and Mitochondrial Signal Transduction Regulate Thermotolerance in Cattle: Insights Into Molecular Mechanisms.
    David Olusola Aderibigbe, Jesse Oluwaseun Ayantoye, Obianwuna Uchechukwu Edna, Osamede Henry Osaiyuwu.
      Heat stress represents a major threat to cattle productivity, welfare, immune competence, and sustainability under climate change. Although genomic studies have identified loci associated with thermoregulatory traits, sequence variation alone does not explain the rapid, reversible cellular adaptations required during acute thermal challenge. Increasing evidence suggests that thermotolerance depends on coordinated regulation between nuclear transcriptional architecture and mitochondrial metabolic stability. This review synthesizes mechanistic insights into two interconnected regulatory axes: heat shock factor 1 (HSF1)-dependent nuclear stress body (nSB) formation and mitochondrial-nuclear signaling. During thermal exposure, HSF1 reorganizes chromatin through phase-separated nuclear condensates, amplifying stress-inducible transcription. Concurrently, mitochondrial perturbation alters reactive oxygen species production, calcium flux, and ATP availability, thereby influencing chromatin accessibility and transcription factor activity. Experimental studies in mammalian systems demonstrate that oxidative signaling modulates HSF1 DNA-binding competence, while mitochondrial metabolites regulate histone acetylation and demethylation, linking energetic status to transcriptional plasticity. These cross-compartmental processes determine whether cells maintain proteostasis and recover or progress toward apoptotic and inflammatory outcomes. Although direct characterization in cattle remains limited, breed-level differences in heat shock protein induction, mitochondrial ROS handling, and mtDNA haplotypes suggest meaningful variation in regulatory resilience. The efficiency of coordination between nuclear activation and mitochondrial stabilization may therefore represent a critical determinant of thermotolerance. We further frame thermotolerance as a resource-allocation trait, reflecting energetic partitioning among milk synthesis, immune function, reproduction, and stress protection in high-producing dairy cattle. Understanding these cross-compartmental regulatory mechanisms may support future studies identifying biomarkers and genomic targets for improving heat resilience in cattle.
    Keywords:  cattle; cattle genomics; climate adaptation; mitonuclear interaction; nuclear stress bodies; thermotolerance
    DOI:  https://doi.org/10.1002/age.70169
  50. Biochem Genet. 2026 Jul 24.
    The m6A Reader IGF2BP2 Suppresses Ferroptosis in Nasopharyngeal Carcinoma by Stabilizing NRF2 mRNA.
    Xiaoyan Xu.
      Nuclear factor erythroid 2-related factor 2 (NRF2) is a central transcriptional regulator of the antioxidant response and a key inhibitor of ferroptosis, and its overexpression is frequently observed in various cancers. However, the mechanisms underlying its dysregulation in nasopharyngeal carcinoma (NPC) remain poorly understood. In this study, we combined bioinformatic analysis with functional experiments to investigate the post‑transcriptional regulation of NRF2 in NPC. Using weighted gene co-expression network analysis (WGCNA) based on the GSE68799 dataset and differential expression analysis of NPC transcriptomic data, we identified NRF2 as a candidate gene associated with NPC progression. Functional studies confirmed that NRF2 inhibits ferroptosis in NPC cells. Mechanistically, we demonstrated that the m6A reader protein insulin‑like growth factor 2 mRNA‑binding protein 2 (IGF2BP2) binds to and stabilizes NRF2 mRNA in an m6A‑dependent manner. Depletion of IGF2BP2 downregulated NRF2 expression and accelerated NRF2 mRNA decay. Notably, inhibition of methyltransferase activity by S-Adenosyl-L-homocysteine (SAH) reduced m6A modification on NRF2 mRNA and impaired its interaction with IGF2BP2. Furthermore, IGF2BP2 knockdown impaired the NRF2/HO-1/GPX4 axis, leading to a significant reduction in GPX4 enzymatic activity and promoted ferroptosis, effects that were rescued by the NRF2 activator dimethyl fumarate (DMF). Collectively, these results reveal that IGF2BP2 stabilizes NRF2 mRNA via m6A modification to suppress ferroptosis, thereby promoting NPC cell survival.
    Keywords:  Ferroptosis; GPX4; HO-1; IGF2BP2; NRF2; Nasopharyngeal carcinoma
    DOI:  https://doi.org/10.1007/s10528-026-11430-1
  51. Nucleic Acids Res. 2026 Jul 17. pii: gkag732. [Epub ahead of print]54(14):
    A novel RNA-binding activity of ECD contributes to U5 snRNP stability and pre-mRNA splicing.
    Mohsin Raza, Asher Rajkumar Rajan, Achyuth Kalluchi, Bhopal Mohapatra, Irfana Saleem, Benjamin B Kennedy, Kishor K Bhakat, Hamid Band, M Jordan Rowley, Vimla Band.
      Human ecdysoneless protein (ECD) plays an essential role in regulating cell cycle progression and cell survival. ECD has previously been implicated in RNA splicing through its association with spliceosomal proteins. Here, using electrophoretic mobility shift assay, fluorescence polarization assays, and mutational analysis, we demonstrate that ECD directly binds to RNA. Enhanced CLIP-seq analysis identified a broad repertoire of mRNAs bound to ECD in cells. RNA-seq analyses revealed that ECD depletion leads to widespread splicing aberrations and altered gene expression. ECD binding to RNAs was enriched near splice sites, and a substantial fraction of ECD-bound transcripts exhibited splicing defects upon ECD depletion. ECD associates with and stabilizes the U5 small nuclear ribonucleoprotein (snRNP) complex specific proteins. While depletion of ECD reduced the levels of key U5-specific proteins, these proteins exhibited an increased association with the R2TP complex in knockout cells. Notably, we found ECD to directly bind to U5 snRNA, and an RNA binding defective mutant of ECD (Δ135-148) failed to rescue the reduced levels of U5-specific proteins or the proliferation defect induced by ECD depletion. Collectively, these findings demonstrate that ECD binds to RNAs, including the U5 snRNA, and that RNA-binding is required for ECD to stabilize the U5 snRNP and for cellular functions.
    DOI:  https://doi.org/10.1093/nar/gkag732
  52. Expert Opin Ther Targets. 2026 Jul 21. 1-16
    APE1/Ref-1: multifunctional biology, selective inhibition, and the path to clinical translation.
    Jessica A Occhiuto, Silpa Gampala, Melissa L Fishel, Mark R Kelley.
       INTRODUCTION: Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1) is a multifunctional stress-response regulator that coordinates genome maintenance, redox signaling, RNA biology, and cellular metabolism. Its expression and subcellular localization further determine disease states and severity. The growing appreciation of its biological complexity and clinical relevance makes APE1/Ref-1 an increasingly attractive therapeutic target for redox-stress-related diseases.
    AREAS COVERED: In this review, we aim to consolidate information on the structural and mechanistic basis of APE1/Ref-1 redox and repair functions, while recognizing emerging evidence in DNA/RNA-forming G-quadruplex (rG4) biology, RNA metabolism, protein homeostasis, and mitochondrial function. We discuss mechanisms regulating APE1/Ref-1 expression, activity, and trafficking, which dynamically influence function in physiological and disease contexts. We specifically emphasize therapeutic strategies including redox-specific inhibition, endonuclease-targeted approaches, and genetic perturbations that result in distinct effects across disease models.
    EXPERT OPINION: Evolving understanding of APE1/Ref-1 biology has accelerated therapeutic development, particularly through redox-selective targeting strategies. Small-molecule inhibitors such as APX3330 and new-generation analogs like APX2009 and APX2014 have advanced into therapeutic applications spanning cancer, inflammatory disorders, and ocular diseases. Continued investigation into the context-dependent and multifunctional roles of APE1/Ref-1, together with the progression of mechanism-informed therapeutic design, is steadily strengthening the translational potential of APE1/Ref-1-directed therapies.
    Keywords:  APE1/Ref-1; cancer therapeutics; diabetic retinopathy; inflammation; inflammatory bowel disease; mitochondrial function; redox-selective inhibition; transcriptional regulation
    DOI:  https://doi.org/10.1080/14728222.2026.2706465
  53. Biochim Biophys Acta Mol Cell Res. 2026 Jul 20. pii: S0167-4889(26)00093-5. [Epub ahead of print]1873(7): 120194
    Orchestration of OXPHOS biogenesis through regulation of mitochondrial translation.
    Andreas Carlström, Carmela Vazquez-Calvo, Martin Ott.
      Mitochondrial gene expression is a remnant of the endosymbiotic origin of the organelle, which contains a complete gene expression system that contributes only a handful of subunits to the complexes driving oxidative phosphorylation (OXPHOS). During evolution, many processes of gene expression in mitochondria have diverged from the bacterial ancestor. A central problem to assemble oxidative phosphorylation complexes is that they contain subunits from two genetic sources. Hence, mechanisms have evolved to synchronize expression of nuclear and mitochondrial genes to avoid problems with stoichiometry, which could hamper their assembly. Here, we will summarize recent insights into how gene expression operates with a focus on the mechanisms related to the control of mitochondrial translation in yeast and human cells.
    Keywords:  Evolution; Gene expression; Mitochondria; Mitoribosomes; Translation initiation; Translational activators; Translational regulation
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120194
  54. Front Cell Dev Biol. 2026 ;14 1855716
    TAF7 accumulates in the cytoplasm during cellular transformation and engages STAT3, WASH, and CCT.
    Dan Cheng, Elizabeth McManus, Ryan M Young, Thomas Oellerich, Bjorn Haupl, Daniel D Billadeau, Hua Tan, Laura Elnitski, Dinah S Singer.
      TAF7, a core subunit of the general transcription factor TFIID, regulates transcription and additionally functions as an RNA chaperone that directs nascent nuclear RNAs to cytoplasmic polysomes, thereby influencing protein synthesis. Here, we identify a set of novel cytoplasmic interactors and a previously unappreciated cytoplasmic role for TAF7 in oncogenesis. BioID-mediated proximity labeling identified STAT3 and the CCT and WASH complexes as prominent cytoplasmic interactors of TAF7. These interactions were validated by co-immunoprecipitation and proximity ligation assays. We further showed that cytoplasmic TAF7 levels increased during oncogenesis in proportion to cancer cell pathogenicity. Notably, TAF7 engagement with STAT3, CCT and WASH complexes is markedly enhanced during cellular transformation, consistent with their functions in cancer progression. Together, these findings reveal a cytoplasmic TAF7 interactome and implicate elevated cytoplasmic TAF7 as associated with oncogenesis.
    Keywords:  CCT; STAT3; WASH; cytoplasmic TAF7; oncogenesis; transformation
    DOI:  https://doi.org/10.3389/fcell.2026.1855716
  55. Nat Commun. 2026 Jul 23. pii: 6179. [Epub ahead of print]17(1):
    Activity-dependent ribosome profiling reveals the landscape of canonical and non-canonical translation in brain tissue.
    Nayan Suryawanshi, Hitoshi Uchida, Ryo Endo, Kai Sato, Daisuke Satoh, Kazuya Tsumagari, Koshi Imami, Takayasu Mikuni, Motomasa Tanaka.
      Neural activity-dependent translation is essential for synaptic plasticity and diverse brain functions. Translation involves not only canonical main open reading frames (mORFs) but also upstream ORFs (uORFs), which may regulate mORF expression. However, due to technical limitations, systematic investigation of activity-dependent uORFs and mORFs in brain tissues remains challenging. Here, we developed a ribosome tagging and purification strategy that bypasses the prolonged turnover of ribosomal proteins, enabling ribosome profiling with one-hour temporal resolution after neural stimulation. Applying this strategy to mouse hippocampal slices undergoing long-term potentiation, we identify hundreds of activity-induced mORFs and uORFs, including a previously unknown uORF from Egr1. We demonstrate that this Egr1-uORF translation is tightly regulated by neuronal activity, and its encoded peptide interacts with peroxisomal machinery, suggesting a potential link between synaptic stimulus and peroxisome biology. This study provides a useful technique and resources for deciphering molecular mechanisms underlying activity- and translation-dependent brain functions in health and disease.
    DOI:  https://doi.org/10.1038/s41467-026-74968-z
  56. Genes Dev. 2026 Jul 23.
    Dual regulation of the unfolded protein response by IGF2BP3 during ER stress.
    Aleksandra S Anisimova, Sabina Omerbegovic, Milica Mihailovic, Sascha Gratzl, Harald Hornegger, Irmgard Fischer, Gijs A Versteeg, Stefan L Ameres, G Elif Karagöz.
      Misfolded protein accumulation in the endoplasmic reticulum (ER) perturbs cellular homeostasis, causing pathological ER stress. While a transcriptional response is paramount for the unfolded protein response (UPR), which counters ER protein stress, multiple UPR-linked mRNAs are posttranscriptionally regulated. However, the mechanisms mediating this regulation remain unclear. Here, we reveal specific interactions between the conserved RNA-binding protein IGF2BP3 and transcripts encoding UPR effectors. During ER stress, IGF2BP3 destabilizes many of its target transcripts, including UPR effectors. Mechanistically, ER stress enhances IGF2BP3's association with the mRNA decapping complex and the ER stress sensor RNase IRE1, which correlates with a shift toward mRNA destabilization. Unexpectedly, prolonged depletion of IGF2BP3 inhibits the UPR via decreased transcription of UPR target genes. Together, our findings suggest that IGF2BP3 contributes to proteostasis during ER stress through a dual mechanism: directly promoting mRNA degradation to reduce translation and folding burden and indirectly supporting transcriptional activation of the UPR.
    Keywords:  IGF2BP3; IRE1; RNA-binding proteins; endoplasmic reticulum; mRNA decapping complex; posttranscriptional regulation; unfolded protein response
    DOI:  https://doi.org/10.1101/gad.353291.125
  57. Hum Reprod Update. 2026 Jul 23. pii: dmag016. [Epub ahead of print]
    Post-translational modification of proteins in the human testis development pathway.
    Firman P Idris, Lucas G A Ferreira, Brendan Houston, Sean J Humphrey, Andrew H Sinclair, Katie L Ayers.
       BACKGROUND: The foetal testes produce the androgens necessary to masculinise the developing embryo and support the maturation of germ cells, that will eventually develop into sperm, thus ensuring future reproductive capacity. The testes develop from the bi-potential gonads in a highly orchestrated process resulting in the differentiation of a complex tissue with multiple cellular lineages. While recent transcriptomic and chromatin-based analyses of human foetal testes have provided an unprecedented level of insight into signalling pathways activated during this process, proteomic studies of the human foetal gonads remain limited. Proteins are active molecules and post-translational modification (PTM) of proteins influences protein activity, stability and localisation. Studies have shown that PTMs regulate critical proteins in testis development, and their disruptions are implicated in congenital disorders including differences of sex development (DSD), in which sex development is atypical. Despite this, the role and regulation of protein PTM during human testis development remains poorly understood due to limited access to human foetal gonadal tissue, a paucity of large-scale proteomics studies, and a lack of robust of human gonad in vitro models.
    OBJECTIVE AND RATIONALE: This review aims to provide a comprehensive analysis of validated PTMs affecting proteins critical for testicular development. We discuss PTMs with evidence for a role in normal testis development, and highlight those disrupted in DSD. We review emerging techniques, including proteomic technologies and organ modelling systems that may advance our understanding of PTMs in foetal testis development. We discuss challenges that have restricted the application of these technologies and how overcoming these will significantly improve our understanding of testis development and disease, diagnostics and patient outcomes.
    SEARCH METHODS: We searched PubMed and the University of Melbourne library for peer-reviewed English-language studies using keywords such as phosphorylation, SUMOylation, acetylation, ubiquitination alongside each protein of interest. PTM sites in proteins involved in testis development were identified using the PhosphoSitePlus database focusing those confirmed in in vitro or animal model studies. ClinVar and the Human Gene Mutation Database were used to identify patient variants that may disrupt PTM sites.
    OUTCOMES: Our review finds that proteins required for human foetal testis development are subject to extensive PTM. Several PTM sites and PTM-mediated pathways [e.g. MAPK (mitogen-activated protein kinase) pathway] are disrupted in patients with DSD or related conditions. While recent advances in proteomics technologies hold considerable promise, their application to human foetal gonads has been constrained by technical, ethical, and logistical challenges. Encouragingly, emerging high-sensitivity and low-input technologies, alongside stem cell-based approaches, offer viable pathways to overcoming these barriers.
    WIDER IMPLICATIONS: The relationship between gene regulation, protein expression, and cellular outcome is inherently non-linear, shaped by additional regulatory layers-most notably PTMs. The contribution of PTMs to human testis development in both typical and atypical contexts is a major knowledge gap. Addressing this gap has broad clinical and biological relevance: it may help improve genetic diagnosis or shed light on how proteins or pathways critical for testis development respond to environmental signals-an increasingly pressing question as declining global fertility rates bring testicular function under greater scrutiny.
    REGISTRATION NUMBER: N/A.
    Keywords:  SUMOylation; acetylation; deacetylation; phosphorylation; post translational modification; sex determination; testis; testis development; ubiquitination
    DOI:  https://doi.org/10.1093/humupd/dmag016
  58. Biochem Pharmacol. 2026 Jul 24. pii: S0006-2952(26)00629-5. [Epub ahead of print] 118290
    The Piezo1/YAP mechanotransduction axis: From mechanistic insights to therapeutic perspectives in disease.
    Ruiming Wen, Haixia Wang, Weifeng Pan, Ziduan Yan, Songtao Wang.
      Cells and tissues are continuously exposed to mechanical cues from their surrounding microenvironment. Mechanobiology investigates how these cues are converted into intracellular biochemical and transcriptional responses. Piezo1, a mechanosensitive cation channel, mediates Ca2+ influx in response to changes in cell membrane tension. This Ca2⁺ signal can influence the activity and subcellular localization of Yes-associated protein (YAP) in a context-dependent manner, thereby contributing to physiological homeostasis and pathological progression. This review specifically focuses on the role of the Piezo1/YAP axis in regulating key physiological processes such as skeletal development, neural plasticity, macrophage polarization, epithelial homeostasis and barrier function, and cardiac development. Under pathological conditions, aberrant mechanical cues such as disturbed shear stress, matrix stiffening, and sustained mechanical overload can activate Piezo1-mediated Ca2⁺ influx and YAP-dependent transcriptional programs, thereby promoting endothelial inflammation, vascular remodeling, tumor cell proliferation, epithelial-mesenchymal transition, metastasis, and degenerative changes in skeletal tissues. Furthermore, this review evaluates emerging intervention strategies targeting the Piezo1/YAP axis, including small-molecule modulators and nanotechnology-based approaches. Although these strategies have shown promise in preclinical studies, their clinical translation remains at an early stage and is limited by challenges related to target specificity, bioavailability, tissue-selective delivery, dosage control, off-target mechanobiological effects, and long-term safety. Overall, this review aims to elucidate the current understanding of the Piezo1/YAP axis from mechanistic insights to therapeutic perspectives, while highlighting the need for further validation before clinical application.
    Keywords:  Bone diseases; Cardiovascular diseases; Mechanotransduction; Piezo1/YAP axis; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.bcp.2026.118290
  59. Mol Syst Biol. 2026 Jul 20.
    qMAP decodes RNA fragmentation dynamics in development and disease.
    Hukam C Rawal, Jiancheng Yu, Xudong Zhang, Chen Cai, Qi Chen, Tong Zhou.
      Noncanonical small RNAs, such as tRNA-derived (tsRNAs) and rRNA-derived (rsRNAs) fragments, are more abundant than microRNAs and arise from selective cleavage events rather than random degradation. While fragmentation of parental RNAs produces functionally diverse small RNAs, current analytical approaches are limited to abundance measures and cannot systematically quantify differential cleavage signals. Here, we present qMAP, a computational framework profiling differential fragmentation of parental RNAs from small RNA sequencing data. qMAP integrates two complementary models to identify condition-specific fragmentation patterns and includes a dedicated module to pinpoint the small RNA species driving these differences. Using qMAP, we uncover dynamic tRNA and rRNA fragmentation during mouse cell reprogramming, demonstrate the classification power of RNA fragmentation in human ulcerative colitis, develop and validate a blood-based RNA fragmentation signature of recurrent implantation failure, and identify aging-associated RNA fragmentation in sperm, which supports RNA fragmentation as a distinct regulatory dimension beyond expression/abundance information. qMAP enables systematic exploration of the regulatory "RNA fragmentome", providing a foundational tool for both mechanistic discovery and translational applications of noncanonical small RNAs.
    DOI:  https://doi.org/10.1038/s44320-026-00237-2
  60. Nat Rev Mol Cell Biol. 2026 Jul 24.
    Mitochondrial tRNA biogenesis, modifications and disease relevance.
    Wen-Yu Zhu, Ilias Skeparnias, Athanasios-Nasir Shaukat, Jinwei Zhang, Ru-Juan Liu.
      The biogenesis, modifications and function of mitochondrial transfer RNAs (mt-tRNAs) reflect the symbiotic relationship and coordinated evolution between the domesticated organelle and the outer cell. Through evolution, mt-tRNA structures have been severely degenerated, and mt-tRNA-associated proteomes have acquired additional domains and interfaces, leveraging post-transcriptional modifications to maintain functional affinity and specificity. Considerable progress has been made in the past decade in elucidating mt-tRNA structure, biogenesis, modifications and functions. In this Review, we outline how mt-tRNAs are excised from polycistronic transcripts and mature through coordinated actions of mitochondrial processing enzymes. We then examine how mitochondrial aminoacyl-tRNA synthetases and mitoribosomes have coevolved to recognize degenerated mt-tRNAs and support a streamlined genetic code. The roles of post-transcriptional modifications in mt-tRNA structure stabilization, mt-tRNA decoding and the coupling of metabolism to translation are also discussed. Moreover, we review mt-tRNA-associated pathologies and emerging therapeutic strategies, highlighting unifying principles that inform efforts to restore coherence of mitochondrial translation.
    DOI:  https://doi.org/10.1038/s41580-026-00999-5
  61. Psychoneuroendocrinology. 2026 Jul 17. pii: S0306-4530(26)00236-2. [Epub ahead of print]192 107976
    Plasma amino acid fluctuations in response to acute psychosocial stress among healthy adults with and without early-life adversity.
    Qiaofeng Ye, Laura Etzel, Abner T Apsley, Aaliya Ahamed, Christopher R Chiaro, Amanda Davis, Waylon J Hastings, John T Kozlosky, Lauren Petri, Idan Shalev.
      Early life adversity (ELA) has been associated with altered amino acid metabolism, which is implicated in physiological functions, but its effects on amino acid dynamics during acute psychosocial stress remain to be investigated. This study utilized within-person between-group experimental design to analyze fluctuations of plasma amino acids across five hours in response to acute psychosocial stress for healthy individuals with and without ELA exposure. Analyses included 33 participants (18-27 years, 55% female, 45% ELA) with 260 time-points of amino acid measurements. Thirteen out of 21 measured amino acids exhibited significant time-varying fluctuations, such that a decrease and subsequent increase were observed before and after a standardized meal. Independent of meal effects, individuals with ELA exhibited faster depletion of phenylalanine and methionine in response to acute stress compared with controls. Furthermore, alanine, tyrosine, betaine, and threonine exhibited greater and lasting depletion among individuals with ELA following acute stress exposure. Amino acids clustered into 4 classes of fluctuation patterns. Class-1 were higher in ELA throughout and declined faster post-stress in ELA. Class-2 exhibited divergent time-varying concentrations between groups in the no-stress session but convergence under stress. Class-3 increased moderately within the first hour but remained mostly stable throughout both sessions. Class-4 exhibited greater stress-related decreases in ELA. Amino acid levels were associated with gene expression patterns related to protein synthesis, mitochondrial constitution, ion channel activity, synaptic signaling, immune functioning, cancer, infection, autoimmunity, immunodeficiency, and neurodevelopmental and psychiatric conditions. Findings suggest alterations in amino acid metabolism may represent a potential pathway linking ELA to stress-related health vulnerability.
    Keywords:  Acute psychosocial stress; Amino acids; Early life adversity; Gene expression; Trier Social Stress Test
    DOI:  https://doi.org/10.1016/j.psyneuen.2026.107976
  62. Acta Naturae. 2026 Apr-Jun;18(2):18(2): 64-75
    Global Changes in Unproductive Splicing and NMD Efficiency in Tumors.
    L G Zavileyskiy, A A Mironov, D D Pervouchine.
      The nonsense-mediated mRNA decay (NMD) pathway is a mRNA quality control mechanism which not only degrades deleterious transcripts but also orchestrates a large number of post-transcriptional regulatory programs through unproductive splicing. We have developed a robust metric derived from splicing quantification in the RNA-seq data to measure NMD efficiency at a sample level. We demonstrate that NMD efficiency varies substantially both between and within tissues, with the magnitude of the variation comparable to that observed upon knockdown of the core NMD factor UPF1. By analyzing TCGA cancer cohorts, we further show that, in many tumors, unproductive splicing events undergo coordinated changes towards either collective suppression or collective activation of NMD isoforms, which is indicative of global deregulation of the activity of the NMD pathway. Consistently, we observed a striking divergence of NMD efficiency in cancers from the tissue-specific baseline level, suggesting that tumors partially erase the NMD signature of their tissue of origin. The application of the developed metric to RNA-binding protein knockdowns made it possible to identify several novel potential regulators of NMD efficiency. In sum, this study provides a solid framework for quantifying NMD efficiency, describes its biological and clinical relevance, and opens new avenues for dissecting mechanisms of post-transcriptional gene expression regulation by the NMD pathway.
    Keywords:  NMD efficiency; Nonsense-mediated decay; regulation; unproductive splicing
    DOI:  https://doi.org/10.32607/actanaturae.27892
  63. Front Immunol. 2026 ;17 1861769
    A multiscale model reveals how ERK/p38-regulated dormancy shapes tumor-immune dynamics and immunoediting outcomes.
    Eti Nyamekeh Baffoe, Anass Bouchnita.
       Introduction: Immune responses in cancer arise from dynamic interactions across biological scales, linking intracellular signaling, cellular phenotypic plasticity, and tumor-immune dynamics. Cancer cell dormancy is increasingly recognized as a continuous and heterogeneous phenotype driven in part by ERK and p38 signaling, yet most existing models represent it as a binary state, limiting their ability to capture its regulatory role in immune-mediated tumor control.
    Methods: Here, we introduce a new ERK-p38-structured model of cancer-immune cells in which tumor cells are continuously stratified along an ERK/p38 phenotypic axis. This framework provides a systems description that preserves both computational efficiency and theoretical tractability. It links intracellular signaling to cellular behavior and population-level dynamics by describing phenotype-dependent proliferation, immune susceptibility, and stress responses driven by growth factors, immune pressure, stress, and therapy.
    Results: Using this model, we show that the distribution of tumor phenotypes governs the emergent regimes of tumor-immune dynamics, including elimination, equilibrium, and escape. The model further predicts that increased p38 activation in response to immune pressure promotes immune evasion, whereas stress-induced p38 signaling drives global tumor dormancy. Conversely, p38 inhibition shifts the phenotype distribution toward more proliferative states, which enhances tumor sensitivity to immune-mediated killing and therapeutic interventions. To provide mechanistic insight, we derive a reduced model and identify critical thresholds in the mean ERK/p38 phenotype that determine tumor fate.
    Discussion: Together, these results suggest that phenotypic plasticity is a key regulator of immunoediting and provide a quantitative multiscale framework linking intracellular signaling to immune-driven tumor dynamics, with implications for understanding immune evasion and improving therapeutic responses.
    Keywords:  dormancy; mathematical modeling; multiscale models; phenotype-structured models; systems immunology
    DOI:  https://doi.org/10.3389/fimmu.2026.1861769
  64. Oncogene. 2026 Jul 23.
    N6-methyladenosine-mediated upregulation of PAICS promotes lung-adenocarcinoma metastasis via the integrin-FAK signaling.
    Mengzhu Zhang, Jianjie Zhu, Huiling Zhang, Jiansheng Zhang, Jian Zhao, Qiongju Chen, Yuanyuan Zeng, Jianjun Li, Jian-An Huang, Zeyi Liu.
      Lung adenocarcinoma (LUAD) is the most common type of lung cancer, often diagnosed in the advanced stage of diffuse metastasis, highly aggressive and rapidly fatal, lacking early diagnostic markers and effective therapeutic targets. Enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) is an important bifunctional enzyme in purine de novo synthesis, and rapidly dividing cancer cells are heavily dependent on de novo synthesis of the adenine and guanine pathways. PAICS has been found to be highly expressed in a variety of cancers and has been shown to promote cancer proliferation or metastasis. However, the specific mechanism of action of PAICS in LUAD is unknown. Our study revealed that PAICS mRNA and protein levels were significantly increased in LUAD tumor tissues compared to adjacent normal tissues. Bioinformatics analysis showed that high PAICS expression was associated with LUAD metastasis and could be used as a factor for diagnosis and assessment of prognosis in LUAD patients. PAICS knockdown suppressed tumor cell migration and invasion, whereas overexpression enhanced these phenotypes. Mechanistically, PAICS promotes tumor metastasis by activating the Focal Adhesion Kinase (FAK) signaling through regulating the expression of Integrin α10 (ITGA10). FAK inhibitor Defactinib (VS6063) successfully inhibited PAICS overexpression-induced lung metastasis in vivo. In addition, we found that the high expression of PAICS in LUAD was regulated by m6A modification. METTL3 (Methyltransferase-like 3) enhances the modification level of PAICS mRNA and IGF2BP2 (Insulin-like growth factor 2 mRNA binding protein 2) binds to its mRNA upon recognition of the m6A modification site, which increased the stability of the mRNA and the expression. These results provide valuable insights into the biological functions of PAICS and potential avenues for new therapeutic approaches.
    DOI:  https://doi.org/10.1038/s41388-026-03917-3
  65. Elife. 2026 Jul 23. pii: RP106716. [Epub ahead of print]14
    Structural dynamics of IRE1 and its interaction with unfolded peptides.
    Elena Spinetti, Grzegorz Ścibisz, Gülsün Elif Karagöz, Roberto Covino.
      The unfolded protein response (UPR) is a crucial signaling network that preserves endoplasmic reticulum (ER) homeostasis, impacting both health and disease. When ER stress occurs, often due to an accumulation of unfolded proteins in the ER lumen, the UPR initiates a broad cellular program to counteract cytotoxic effects. Inositol-requiring enzyme 1 (IRE1), a conserved ER-bound protein, is a key sensor of ER stress and activator of the UPR. While biochemical studies confirm IRE1's role in recognizing unfolded polypeptides, high-resolution structures showing direct interactions remain elusive. Consequently, the precise structural mechanism by which IRE1 senses unfolded proteins is debated. In this study, we employed advanced molecular modeling and 137 µs of atomistic molecular dynamics simulations to clarify how IRE1 detects unfolded proteins. Our results demonstrate that IRE1's luminal domain directly interacts with unfolded peptides and reveal how these interactions can stabilize higher-order oligomers. We provide a detailed molecular characterization of unfolded peptide binding, identifying two distinct binding pockets at the dimer's center, separate from its central groove. Furthermore, we present high-resolution structures illustrating how BiP associates with IRE1's oligomerization interface, thus preventing the formation of larger complexes. Our structural model reconciles seemingly contradictory experimental findings, offering a unified perspective on the diverse sensing models proposed. We elucidate the structural dynamics of unfolded protein sensing by IRE1, providing key insights into the initial activation of the UPR.
    Keywords:  IRE1; S. cerevisiae; UPR; endoplasmic reticulum; human; molecular biophysics; structural biology
    DOI:  https://doi.org/10.7554/eLife.106716
  66. Adv Sci (Weinh). 2026 Jul 23. e76593
    Microprotein MP104 Promotes Malignant Progression of Colorectal Cancer Through Regulating Protein Translation.
    Fang Chen, Miao Wang, Hongmei Yong, Jin Ding, Shiping Xu, Qirui Ge, Yan Wang, Lei Zhang, Qianqian Xiao, Benli Li, Li Lin, Sufang Chu, Qianqing Wang, Jin Bai, Pingfu Hou.
      Colorectal cancer (CRC) remains a major cause of cancer mortality, necessitating the identification of novel oncogenic drivers. We report the discovery of MP104, a 104-amino acid microprotein encoded by the long non-coding RNA ZEB1-AS1, which is endogenously expressed and upregulated in CRC with strong association to poor prognosis. Functional assays revealed that MP104 promotes CRC cell proliferation, migration, invasion, and metastasis. Mechanistically, MP104 interacts with UBE2O to facilitate AMPKα2 ubiquitination and degradation, thereby activating mTOR signaling. This activation enhances EIF4B phosphorylation and stability, while MP104 further inhibits RNF40-mediated EIF4B ubiquitination, collectively sustaining translational upregulation. Thus, MP104 drives CRC progression primarily through reprogramming protein translation via the UBE2O-AMPKα2-mTOR-EIF4B axis, establishing it as a key regulator of oncogenic translational control and a promising biomarker and therapeutic target in CRC.
    Keywords:  UBE2O‐AMPKα2‐mTOR‐EIF4B axis; ZEB1‐AS1; colorectal cancer; microprotein MP104; protein translation regulation
    DOI:  https://doi.org/10.1002/advs.76593
  67. Sci Adv. 2026 Jul 24. 12(30): eaeg2060
    Hdac3 suppresses apoptosis through deacetylating and stabilizing the antiapoptotic protein Diap1.
    Dafa Zhou, Bin Liu, Yan Ding, Yujiao Wang, Yuanfei Sun, Simin Xu, Hui Li, Xiaopei Wang, Yunhe Zhao, Qingxin Liu, Zizhang Zhou.
      Apoptosis is a highly conserved process that eliminates unwanted or damaged cells in both physiological and pathological conditions. Dysregulation of apoptosis leads to developmental abnormalities and various diseases, such as neurodegeneration and cancer. Drosophila inhibitor of apoptosis 1 (Diap1) plays a crucial role in cell survival by inhibiting caspases and preventing apoptosis. However, under stress conditions, the prodeath proteins Rpr, Hid, and Grim (RHG) induce apoptosis by antagonizing Diap1. Despite being a key component of the apoptotic pathway, the mechanism that controls the stability of Diap1 remains unknown. Here, we find that loss of hdac3 results in the activation of apoptosis, which is completely blocked by expressing Diap1. Although Hdac3 localizes in both the cell cytoplasm and nucleus, only the cytoplasmic Hdac3 is able to suppress apoptosis induced by hdac3 deficiency, RHG overexpression, or x-ray irradiation. This finding indicates that Hdac3 exerts an antiapoptotic role independent of its canonical epigenetic functions. Loss of hdac3 decreases Diap1 protein, which is rescued by introducing cytoplasmic Hdac3. The deacetylase activity is necessary for Hdac3 to suppress apoptosis. Mechanistically, Hdac3 interacts with Diap1 to remove the acetyl group from K315 on Diap1, thereby increasing its stability. Compared with the wild-type Diap1, the acetyl-deficient mutant Diap1-K315R exhibits stronger stability and antiapoptotic activity. Last, RHG proteins compete with Hdac3 for Diap1 interaction, directing Diap1 toward degradation and triggering apoptosis. Together, these findings not only reveal the involvement of Diap1 acetylation modification in apoptosis regulation but also clarify the role of Hdac3 in apoptosis.
    DOI:  https://doi.org/10.1126/sciadv.aeg2060
  68. J Cell Sci. 2026 Jul 15. pii: jcs264633. [Epub ahead of print]139(14):
    Annulate lamellae - an underexplored cellular structure.
    Lizanne Oliveira, Jomon Joseph.
      Annulate lamellae (AL) are endoplasmic reticulum (ER) subdomains harbouring a subset of nucleoporins (Nups), the proteins that assemble into the nuclear pore complexes (NPCs) on the nuclear envelope (NE). AL have been observed in a variety of cell types, including oocytes, spermatids, embryonic cells, somatic cells and tumour cells, as well as in multiple cell lines. Some studies propose that AL derive from the NE, whereas studies in Drosophila egg chambers indicate that AL can assemble through differential condensation of soluble Nups, thus implying that modes of AL assembly can vary depending on the cell type and cell physiology. Although little is known about the functions of AL, they have conventionally been implicated in NPC assembly and NE homeostasis. However, emerging evidence suggests additional roles for AL in the regulation of nucleocytoplasmic transport (NCT) and mRNA translation. Additionally, AL might regulate cytosolic processes such as ER-mitochondrial connectivity, ER Ca2+ release, and activation of specific proteins. AL remodelling is also associated with development, disease and infection, further emphasising a key role for AL in a variety of cellular processes and contexts.
    Keywords:  Acute necrotizing encephalopathy-1; Annulate lamellae; Ca2+ homeostasis; ERMCS; ER–mitochondria contact site; NPC; NPC-phagy; Neurodegenerative diseases; Nuclear pore complex; Nucleocytoplasmic transport; Nucleoporins; Nups; miRNA
    DOI:  https://doi.org/10.1242/jcs.264633
  69. Crit Rev Oncol Hematol. 2026 Jul 18. pii: S1040-8428(26)00383-5. [Epub ahead of print]226 105496
    Mechanistic analysis and clinical translation strategies of m6A erasers in the metabolism-immunity axis of hepatocellular carcinoma.
    Qin Wen, Chenyang Liu, Chaofan Li, Xingxing Yuan.
      Hepatocellular carcinoma (HCC) is a malignant tumor with high heterogeneity and immunotherapeutic resistance worldwide, presenting a severe challenge in clinical prevention and treatment. N6-methyladenosine (m6A) is the most common reversible post-transcriptional modification on eukaryotic mRNA, whose dynamic balance is precisely regulated by "demethylases" (Erasers). Recent studies have confirmed that the two core m6A Erasers (FTO and ALKBH5) exhibit significant expression imbalance in HCC, which strongly drives malignant tumor progression. Erasers enhance the ferroptosis resistance of HCC cells by regulating the stability of lipid metabolism-related RNAs such as GPNMB and FLAD1, helping them adapt to adverse metabolic microenvironments such as hypoxia and nutrient deprivation. Meanwhile, FTO can promote exosome release, inhibit the antigen-presenting function of dendritic cells (DCs), and further induce CD8⁺ T cells into an exhausted state. These processes synergistically construct an immunosuppressive tumor microenvironment (TIME), facilitating HCC to escape immune attack. Small-molecule inhibitors targeting core targets such as FTO and the emerging PROTAC technology have shown potential in preclinical models for reversing immunosuppression and enhancing the efficacy of systemic therapy. This review systematically synthesizes the regulatory mechanisms of Erasers in the HCC "metabolism-immunity" axis, comprehensively summarizes Eraser intervention strategies based on different etiological backgrounds for the first time, and concludes the clinical translation progress of related targeted drugs, providing new ideas and targets at the epitranscriptomic level for overcoming HCC immunotherapeutic resistance.
    Keywords:  Hepatocellular carcinoma; M(6)A demethylase; Metabolism-immunity axis; N6,2’-O-dimethyladenosine; PROTAC technology
    DOI:  https://doi.org/10.1016/j.critrevonc.2026.105496
This page is being maintained by Thomas Krichel. It was last updated on 2026‒07‒26 at 5:24.