Cell Biology and Toxicology最新文献

{"title":"Post-transcriptional activation of TGF-β signaling via SMAD mRNA stabilization by EIF4A3 promotes EMT and metastasis in gastric cancer.","authors":"Yujing Liu, Yanhua Zhang, Wenhuan Dou, Wei Peng, Ming Cheng, Yan Zhou, Qiankun Shao, Yongyou Wu","doi":"10.1007/s10565-026-10171-6","DOIUrl":"10.1007/s10565-026-10171-6","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) is characterized by high mortality due to late-stage diagnosis and aggressive metastatic behavior. Epithelial-mesenchymal transition (EMT), primarily driven by the TGF-β/SMAD signaling, critically contributes to GC progression. However, the molecular mechanisms regulating this pathway remain incompletely understood.</p><p><strong>Methods: </strong>We investigated the expression, function, and regulatory mechanisms of EIF4A3 in GC using patient tissues, GC cell lines, and in vivo mouse models. We performed loss-of-function experiments and xenograft studies to assess the biological effects of EIF4A3. Mechanistic studies were applied for exploring the relation between EIF4A3 and TGF-β/SMAD signaling.</p><p><strong>Results: </strong>EIF4A3 upregulation was observed in GC samples as well as cell lines compared to normal counterparts, and indicated advanced clinical stages and poor clinical outcomes. EIF4A3 knockdown markedly repressed GC cell growth and DNA synthesis in vitro, while restraining tumor growth and Ki67 expression in xenograft models. Silencing EIF4A3 impaired cell migration, invasion, and lung metastasis, and reversed TGF-β induced EMT marker expression. Mechanistically, TGF-β1 transcriptionally induced EIF4A3 via SMAD2/3 binding to its promoter. In turn, EIF4A3 enhanced TGF-β/SMAD signaling by directly binding to and stabilizing SMAD2, SMAD3, and SMAD4 mRNAs, prolonging their half-lives and promoting their phosphorylation and nuclear accumulation. Furthermore, EIF4A3 knockdown reduced SMAD2/3 phosphorylation, nuclear translocation, and downstream EMT marker expression, thereby attenuating the pro-metastatic effects of TGF-β signaling.</p><p><strong>Conclusions: </strong>Our study identifies EIF4A3 as a critical post-transcriptional regulator and downstream effector of the TGF-β/SMAD pathway. EIF4A3 forms a positive feedback loop with TGF-β/SMAD signaling, thereby reinforcing EMT and promoting metastatic progression in GC. These findings establish EIF4A3 as a novel post-transcriptional amplifier of TGF-β signaling and a promising candidate for diagnostic and therapeutic intervention in metastatic GC.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13186813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147653852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CK1-induced TERT phosphorylation mediates mitochondrial translocation to inhibit cardiomyocyte senescence and alleviate myocardial ischemia-reperfusion injury.","authors":"Zheng Wan, Yi Lu, Hui Wang, Yanchun Ding","doi":"10.1007/s10565-026-10172-5","DOIUrl":"10.1007/s10565-026-10172-5","url":null,"abstract":"<p><strong>Background: </strong>Cellular senescence is an outcome of mitochondrial dysfunction occurring during myocardial ischemia/reperfusion injury (MIRI). Mitochondrial telomerase reverse transcriptase (TERT) is responsible for cardiac protection and can improve MIRI. In this study, the effects of TERT on cardiomyocyte senescence after MIRI were evaluated.</p><p><strong>Methods: </strong>Infarct area was examined by EVANS BLUE and TTC combined staining in MIRI mice. HE staining evaluated myocardial injury. Ultrasound electrocardiogram was used to detect cardiac function in mice. mRNA expression of TERT and CK1 was assessed utilizing RT-qPCR. Protein levels of SA-β-gal, TERT, p-TERT and CK1 were measured by Western blot. Mitochondrial membrane potential was determined by JC-1. Immunofluorescence staining detected the expression and localization of p-TERT. Co-immunoprecipitation (Co-IP) determined interaction between CK1 and TERT. Changes in senescence-associated secretory phenotype (SASP) were detected by ELISA assay. Mouse primary cardiomyocytes were exposed to oxygen and glucose deprivation/reoxygenation (OGD/R) condition. Cell viability was assessed by CCK-8.</p><p><strong>Results: </strong>In MIRI mice, cardiomyocytes showed increased levels of mitochondrial dysfunction and cellular senescence. After MIRI, mitochondrial aggregation of p-TERT diminished in cardiomyocytes, whereas nuclear aggregation increased. TERT depletion exacerbated myocardial damage in MIRI mice. TERT silencing advanced MIRI progression by enhancing mitochondrial dysfunction and cellular senescence in cardiomyocytes. CK1 phosphorylated TERT at serine 227 and controlled mitochondrial relocation of TERT. CK1 alleviated MIRI and reduced cellular senescence by phosphorylating TERT in mice.</p><p><strong>Conclusion: </strong>CK1 regulates TERT phosphorylation and mitochondrial translocation to suppress mitochondrial dysfunction and cell senescence after MIRI, which provides new therapeutic targets for MIRI treatment.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13186895/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147653878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ZRANB1 depletion inhibits neuroblastoma progression by destabilizing MYCN through EZH2-mediated deubiquitination.","authors":"Zhichao Wang, Long Cheng, Guanghui Li, Huiyan Cheng","doi":"10.1007/s10565-026-10186-z","DOIUrl":"10.1007/s10565-026-10186-z","url":null,"abstract":"<p><strong>Background: </strong>Neuroblastoma (NB) is a common malignant solid tumor in children, notably aggressive in cases with MYCN amplification. Unraveling the mechanisms behind NB progression is crucial for developing targeted therapies. ZRANB1, a deubiquitinating enzyme, has emerged as a significant player in many cancers, but its specific function in NB still to be fully elucidated.</p><p><strong>Methods: </strong>Bioinformatic analyses of transcriptomic datasets (GSE85047 and GSE80149) were performed to identify potential MYCN-dependent pro-survival genes. The biological functions of ZRANB1 in NB cells were assessed by CCK-8, colony formation, migration, invasion, and tumor sphere formation assays. Co-IP, Western blot, CHX chase, and ubiquitination assays were performed to assess the regulatory relationship among ZRANB1, EZH2, and MYCN. Catalytically inactive ZRANB1 mutant and in vitro pull-down assays were performed to validate the requirement of deubiquitinase activity and direct interactions. We evaluated the contribution of the ZRANB1-EZH2-MYCN axis to tumor growth using cell-based assays and mouse xenograft models.</p><p><strong>Results: </strong>ZARNB1 was substantially higher in MYCN-amplified BE(2)M17 cell lines. Functional studies demonstrated that ZRANB1 promoted proliferation, migration, and tumorigenicity. Mechanistically, although ZRANB1 did not directly bind MYCN, it formed a ternary complex with EZH2 and MYCN, thereby stabilizing MYCN via EZH2-mediated regulation. Deubiquitinase activity was required for ZRANB1-mediated MYCN stabilization, and direct ZRANB1-EZH2 interaction was confirmed by in vitro pull-down assays.</p><p><strong>Conclusions: </strong>This study identifies ZRANB1 as an upstream deubiquitinase that stabilizes EZH2, thereby indirectly maintaining MYCN stability in MYCN-amplified neuroblastoma. These findings establish a ZRANB1-EZH2-MYCN regulatory axis and highlight ZRANB1 as a promising therapeutic target in MYCN-amplified NB.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13315476/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632438","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanism of uptake and toxicity of a BCMA antibody drug conjugate with a MMAF payload by nonantigen expressing cells.","authors":"Carla Newman, Chloe Taylor, Gurpreet Sohanpal, Tanja Högg, James Kennedy, Eliot McKinley, Elena Koudouna, Edward J Sayers, Arwyn T Jones, Peter Watson, Lucinda Weir","doi":"10.1007/s10565-026-10183-2","DOIUrl":"10.1007/s10565-026-10183-2","url":null,"abstract":"<p><p>Belantamab mafodotin, an antibody-drug conjugate (ADC), has shown strong efficacy in multiple myeloma. It comprises a humanized anti-B-cell maturation antigen (BCMA) IgG1 monoclonal antibody conjugated to the microtubule inhibitor monomethyl auristatin F (MMAF) via a protease-resistant maleimidocaproyl linker. Ocular-related adverse events, particularly corneal events, have been reported with MMAF-containing ADCs, including belantamab mafodotin, through unknown mechanisms. This study investigated the mechanism of uptake and cytotoxicity with belantamab mafodotin in non-BCMA-expressing primary human corneal epithelial cells (HCEC), renal proximal tubule cells (RPTEC) to better understand the etiology of corneal events. ADC uptake into HCEC and RPTEC was concentration and time dependent. Results indicated uptake and traffic into the endocytic pathway, and ADC cleavage to release cys-mcMMAF leading to breakdown of the microtubule network and apoptosis, with greater uptake and cytotoxicity in HCEC versus RPTEC. ADC uptake was significantly reduced (~ 23%) following treatment with the macropinocytosis inhibitor 5-(N-Ethyl-N-isopropyl)amiloride. Co-treatment with endocytic pathway inhibitors nystatin or chlorpromazine also reduced ADC uptake, while siRNA depletion of specific endocytic pathways showed no consistent effects on uptake in HCEC. These in vitro data indicate BCMA-independent macropinocytosis plays a role in belantamab mafodotin uptake by HCEC, leading to cell death consistent with the inhibition of tubulin polymerization, the mechanism of MMAF toxicity. However, the precise mechanism of uptake requires further research. Treatment of cells with human immunoglobulin solution reduced belantamab mafodotin uptake in HCEC, protected nuclei count, and significantly reduced apoptosis and should be explored further.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13342044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147638034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mitochondrial dynamics and cancer: mechanisms and targeted therapy.","authors":"Aixin Wang, Xinyu Ye, Yumeng Zhao, Chao Zhang","doi":"10.1007/s10565-026-10174-3","DOIUrl":"10.1007/s10565-026-10174-3","url":null,"abstract":"<p><p>Mitochondria, as key organelles in eukaryotic cells, regulate cellular energy homeostasis and functional integrity through dynamic processes, including fission, fusion, autophagy, and transport, underpinned by precise molecular mechanisms. In healthy cells, the equilibrium of mitochondrial dynamics ensures network quality control and metabolic coordination. In contrast, cancer cells exhibit multi-dimensional dysregulation characterized by hyperactive fission, impaired fusion, and compensatory upregulation of respiratory chain assembly factors, creating a state of \"morphology-function decoupling\". These alterations drive tumor progression by reprogramming cellular metabolism, promoting proliferation, inhibiting apoptosis, enhancing migration and drug resistance, and facilitating immune evasion. This review elucidates the molecular mechanisms underlying mitochondrial dynamics, their dysregulation in cancer, and their influence on tumor behavior, while also addressing the core challenges of current targeted therapeutic strategies and the novel therapeutic paradigm of \"network remodeling\", offering new insights into tumor biology and precision cancer therapy.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13186849/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147621777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics analysis and experimental validation reveal the IRF7-CXCL10 axis as a master regulator of microglial PCD in ischemic stroke.","authors":"Yongxing Lai, Peiqiang Lin, Kexin Zhang, Wenyao Hong, Mouwei Zheng, Lijuan Wu, Tin Chen, Fan Lin","doi":"10.1007/s10565-026-10177-0","DOIUrl":"10.1007/s10565-026-10177-0","url":null,"abstract":"<p><strong>Background: </strong>Microglia-driven neuroinflammation serves as a critical factor in secondary injury following ischemic stroke, yet the primary regulators governing detrimental microglial phenotypes remain unclear. As a key component of this process, the cell type-specific regulatory mechanisms of programmed cell death (PCD) are poorly understood.</p><p><strong>Methods: </strong>We performed an integrative analysis of public single-cell and bulk transcriptomic datasets from a murine stroke model. A multi-layered computational pipeline, incorporating pseudotime trajectory, weighted co-expression network analysis (WGCNA), and gene regulatory network inference (SCENIC), was used to identify master regulators of PCD. Functional validation was conducted using in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) on primary microglia-neuron co-cultures and in vivo via a transient middle cerebral artery occlusion (tMCAO) model, employing AAV-mediated microglia-specific gene silencing, comprehensive in vitro and in vivo rescue strategies, and detailed behavioral assessments.</p><p><strong>Results: </strong>Our single-cell analysis identified microglia as the central hub of PCD activity post-stroke. An unbiased, multi-layered computational pipeline converged upon Interferon Regulatory Factor 7 (IRF7) as the master transcriptional regulator of this high-PCD, pathological microglial state. We confirmed IRF7 upregulation in microglia following ischemic injury and delineated a novel downstream pathway where IRF7 directly binds the CXCL10 promoter to drive its expression, promoting microglial dysfunction and neurotoxicity. In vitro, silencing IRF7 skewed microglia toward an anti-inflammatory phenotype and protected co-cultured neurons from apoptosis. Critically, microglia-specific IRF7 knockdown in vivo significantly reduced infarct volume, suppressed neuronal death, and led to significant improvements in long-term neurological and cognitive function after stroke. Crucially, both in vitro genetic overexpression of CXCL10 and in vivo administration of recombinant CXCL10 completely abolished the neuroprotective benefits of IRF7 inhibition, establishing a definitive functional causality for the IRF7-CXCL10 axis.</p><p><strong>Conclusion: </strong>Our findings uncover the IRF7-CXCL10 axis as a pivotal driver of detrimental neuroinflammation in ischemic stroke and establish IRF7 as a potent therapeutic target for neuroprotection.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13186846/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147621898","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The PRKN/METTL3/CLDN2 axis promotes colorectal cancer development through epigenetic mechanisms.","authors":"Hongtao Ren, Mincong Wang, Xiulong Ma, Lei An, Yuyan Guo, Hongbing Ma","doi":"10.1007/s10565-026-10180-5","DOIUrl":"10.1007/s10565-026-10180-5","url":null,"abstract":"<p><strong>Background: </strong>Dysregulation of N6-methyladenosine (m6A) RNA methylation plays a crucial role in colorectal cancer (CRC) development. Despite the established oncogenic role of methyltransferase-like 3 (METTL3) in CRC, the mechanisms behind its tumor-promoting functions are not fully understood.</p><p><strong>Methods: </strong>Functional impacts were assessed by measuring cell viability, invasion, colony formation, migration, apoptosis, and M2 macrophage polarization in vitro, as well as in vivo tumorigenicity. The interaction between METTL3 and claudin 2 (CLDN2) was validated via RNA immunoprecipitation and luciferase assays. The PRKN/METTL3 interaction was analyzed using immunoprecipitation (IP) and Co-IP experiments. The stability of mRNA and protein levels was examined by treating cells with actinomycin D or cycloheximide.</p><p><strong>Results: </strong>METTL3 and CLDN2 levels were upregulated in CRC samples and cells. Depletion of METTL3 or CLDN2 suppressed CRC cell proliferation, invasion, and migration, and inhibited M2 polarization of THP-1-derived macrophages. Mechanistically, METTL3 promoted m6A methylation and stability of CLDN2 mRNA in an insulin-like growth factor 2 binding protein 2 (IGF2BP2)-dependent manner. METTL3 silencing diminished CRC cell malignant phenotypes and M2 macrophage polarization via CLDN2 reduction. Moreover, PRKN enhanced METTL3 protein degradation through K63-linked polyubiquitination. The PRKN/METTL3 axis regulated malignant phenotypes of CRC cells. Additionally, METTL3 depletion repressed tumor growth and lung metastasis of xenografts in vivo via CLDN2.</p><p><strong>Conclusion: </strong>Our work uncovers a previously unrecognized PRKN-METTL3-CLDN2 signaling network that orchestrates colorectal tumorigenesis, providing a compelling rationale for developing METTL3-targeted therapies against CRC.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13171652/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147589852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N-nitrosodimethylamine induces cytochrome P450 activation but not epithelial remodeling in well-differentiated human airway epithelial cells.","authors":"Faria Khan, Megan E Solan, Hyo Jin Kim, Christa Wright, Jin-Ah Park","doi":"10.1007/s10565-026-10181-4","DOIUrl":"10.1007/s10565-026-10181-4","url":null,"abstract":"<p><p>N-nitrosodimethylamine (NDMA) is a volatile environmental contaminant formed from diverse precursor chemicals widely present in byproducts of industrial processes, personal care products, and pharmaceuticals. Therefore, NDMA is frequently detected in both indoor and outdoor air. However, its potential risk from inhalation exposure has been largely underestimated and the mechanisms underlying its toxicity remain insufficiently studied. To address this knowledge gap, we investigated the effects of NDMA on primary human bronchial epithelial (HBE) cells differentiated in air-liquid interface cultures, a physiologically relevant in vitro model that mimics the structure and function of the human airway epithelium. To determine time and dose-dependent responses, we exposed well-differentiated HBE cells to NDMA at increasing concentrations (0.05 - 5 mM) either basolaterally for up to 24 h or apically for 4 h daily over 1, 3, or 5 days. We then assessed cellular responses linked to epithelial cell functions, including cell viability, epithelial-to-mesenchymal transition (EMT), epithelial junction integrity, and xenobiotic metabolism, focusing on cytochrome P450 (CYP450) enzyme. NDMA exposure at concentrations up to 5 mM did not affect cell viability under any tested conditions. Similarly, we observed no evidence of EMT, as determined by mRNA expression of vimentin and ZEB1, and no disruption of epithelial junctions, as indicated by preserved expression and localization of E-cadherin and ZO-1. In contrast, 5 mM NDMA significantly increased mRNA expression and enzymatic activity of CYP450 in a time-dependent manner over 5 days. Together these data indicate that NDMA activates epithelial metabolic pathways in the absence of EMT or epithelial remodeling.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13061804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147589893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALKBH5/IGF2BP1-mediated m⁶A demethylation of TRIM37 promotes pancreatic cancer tumorigenesis and glycolysis by mediating RBMX degradation.","authors":"Cheng Yan, Xuan Li, Ying Zhao, Jinhui Chen, Xinke Peng, Daichao Wu, Yabin Chang, Guodong Chen","doi":"10.1007/s10565-026-10173-4","DOIUrl":"10.1007/s10565-026-10173-4","url":null,"abstract":"<p><strong>Background: </strong>The upregulation of the ubiquitin ligase TRIM37 is associated with an adverse prognosis in pancreatic ductal adenocarcinoma (PDAC). This study investigates the mechanism and oncogenic consequence of TRIM37 upregulation in PDAC development.</p><p><strong>Methods: </strong>TRIM37 expression was assessed by qPCR and Western blotting. The effects of TRIM37 knockdown and overexpression on cell proliferation, colony formation, stemness capacity was investigated through in vitro assays, and the role in PDAC was evaluated through vivo experiments. RNA immunoprecipitation assay and Actinomycin D assay were performed to detect the mechanism of TRIM37 upregulation. The TRIM37 and RBMX interaction were determined through co-immunoprecipitation and immunofluorescence.</p><p><strong>Results: </strong>We identified TRIM37 as a critical oncoprotein in PDAC, and its overexpression was strongly correlated with poor prognosis. As a ubiquitin ligase, TRIM37 targets the tumor suppressor RBMX for proteasomal degradation, promoting glycolytic reprogramming and driving aggressive cancer phenotypes, including enhanced proliferation, migration, and stemness. Furthermore, we found that the ALKBH5-IGF2BP1 axis promotes TRIM37 expression by controlling N6-methyladenosine (m⁶A) modification of TRIM37 mRNA and enhancing its transcript stability.</p><p><strong>Conclusions: </strong>Our findings establish the ALKBH5/IGF2BP1-TRIM37-RBMX signaling axis as a pivotal driver of PDAC progression, highlighting the intersection of m⁶A modification, ubiquitin signaling, and metabolic reprogramming. These findings may provide potential therapeutic avenues for this intractable malignancy.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13167913/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147589849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of m⁶A modifications in Th2-driven allergic responses: impact on responses and therapeutic potential.","authors":"Meng Wang, Yunxiu Wang, Zhiwei Cao, Zhaowei Gu","doi":"10.1007/s10565-026-10175-2","DOIUrl":"10.1007/s10565-026-10175-2","url":null,"abstract":"<p><p>Th2-driven allergic responses are characterized by allergic reactions and immune dysregulation with complex pathogenesis that warrants urgent in-depth study. The predominant posttranscriptional modification observed in eukaryotic messenger RNAs, N6-methyladenosine (m⁶A), dynamically regulates RNA splicing, which is likely regulated during cell fate determination, cytokine production, and epithelial barrier maintenance in context of Th2-driven allergic responses. This review systematically analyzes the effects of m⁶A modification on the differentiation and functional regulation of major immune cell populations, including dendritic cells, macrophages, T helper cells, B cells, and mast cells, as well as barrier-forming epithelial cells. Additionally, we discuss how m⁶A regulators control the transcription of cytokine-encoding genes, transcription factors that regulate T-cell function, and T lymphocyte activation signals. Furthermore, this paper integrates the latest research advancements and explores the application potential of m⁶A modification for diagnosis and treatment of Th2-driven allergic disorders, including allergic asthma and rhinitis. By presenting a summary of the current progress in this area of research, this paper aims at summarizing the role of m⁶A modification during Th2-driven allergic responses and highlight its therapeutic potential and future research directions.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":" ","pages":""},"PeriodicalIF":5.7,"publicationDate":"2026-03-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13158254/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147580786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}