Cell Biology and Toxicology最新文献

{"title":"Therapeutic targeting of PRSS3 to alleviate kidney damage in DKD.","authors":"Rui Yang, Rongping Chen, Ningning Xu, Xiaoyan Yang, Hong Chen","doi":"10.1007/s10565-025-10060-4","DOIUrl":"10.1007/s10565-025-10060-4","url":null,"abstract":"<p><strong>Background: </strong>As a primary contributor to end-stage renal disease, diabetic kidney disease (DKD) is characterized by metabolic and inflammatory disturbances. Emerging evidence highlights the gut microbiota's contribution to DKD through metabolite interactions. This study investigates the role of the gut microbiota-derived metabolite trimethylamine-N-oxide (TMAO) and its inhibition of the protease serine 3 (PRSS3) gene in DKD progression.</p><p><strong>Methods: </strong>Fecal and blood samples from 22 DKD and 22 non-diabetic kidney disease (NDKD) patients were analyzed using 16S rRNA sequencing and LC/MS-based metabolomics. Differential gene expression was analyzed using public datasets. Molecular docking assessed TMAO-PRSS3 interactions. In vitro studies employed high-glucose treatments and TMAO exposure in HK-2 renal epithelial cells, while in vivo DKD models were induced in mice using streptozotocin. Functional roles of PRSS3 were validated through lentiviral overexpression and adeno-associated virus delivery.</p><p><strong>Results: </strong>Gut microbiota analysis revealed reduced diversity and abundance in DKD patients, with altered bacterial taxa associated with increased TMAO production. Metabolomics identified TMAO as a significant metabolite, targeting PRSS3 and reducing its expression in renal cells. Molecular docking confirmed direct TMAO-PRSS3 binding. PRSS3 overexpression mitigated high-glucose- and TMAO-induced renal cell damage and inflammation in vitro and fibrosis in DKD mouse models. However, TMAO partially attenuated PRSS3's protective effects.</p><p><strong>Conclusions: </strong>This study identifies TMAO as a key mediator of DKD progression through PRSS3 inhibition. Enhancing PRSS3 expression protects against renal damage, highlighting its potential as a therapeutic target. Modulating gut microbiota and TMAO levels offers promising avenues for DKD management.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"108"},"PeriodicalIF":5.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12202676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144494751","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":"ADT increases prostate cancer cell invasion via altering AR/SALL4/SOX2-OCT4 stem cell signaling.","authors":"Changcheng Guo, Aimaitiaji Kadier, Zhijin Zhang, Shiyu Mao, Bin Yang, Junhua Zheng, Xudong Yao","doi":"10.1007/s10565-025-10046-2","DOIUrl":"10.1007/s10565-025-10046-2","url":null,"abstract":"<p><p>Early studies indicated that the androgen-deprivation-therapy with antiandrogen Enzalutamide (Enz) could increase prostate cancer patients' survival by an average of 4.8 months. Yet Enz might also have some adverse effects via increasing the prostate cancer (PCa) cell invasion. Here we found Enz treatment could increase SALL4 expression to increase the cancer stem cells-like (CSC-like) population that resulted in increasing the PCa cell invasion. Mechanism dissection revealed that Enz could function via androgen receptor (AR) to transcriptionally regulate the SALL4 expression via direct binding on the SALL4 5'-promoter. The consequences of such Enz/AR/SALL4 axis could upregulate the SOX2-OCT4 expression to increase the CSC-like population and the PCa cells invasion. Together, results from multiple in vitro and in vivo experiments all conclude that Enz may induce the adverse effect of increasing PCa cells invasion via altering the AR/SALL4/SOX2-OCT4 signaling to increase the CSC-like population, and targeting SALL4 may decrease this adverse effect for further suppress the PCa progression.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"107"},"PeriodicalIF":5.3,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12176959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144324502","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 role of lncRNA HUPCOS in androgen metabolism and follicle growth arrest in polycystic ovary syndrome.","authors":"Jun Xie, Xiao Xu, Yuning Chen, Yongning Lu, Miao Liu, Yi Feng, Che Qi, Suying Liu","doi":"10.1007/s10565-025-10047-1","DOIUrl":"10.1007/s10565-025-10047-1","url":null,"abstract":"<p><strong>Background: </strong>Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and follicular growth arrest. This study investigates the role of a newly identified long non-coding RNA, lncRNA-ZSCAN2-5:15 (HUPCOS), in the dysregulation of androgen metabolism and ovulatory function.</p><p><strong>Methods: </strong>Clinical samples from 47 PCOS patients and 68 controls undergoing intracytoplasmic sperm injection were analyzed. Follicular fluid hormone levels and granulosa cell expression of HUPCOS, CYP19 A1, and SMAD4 were measured. A PCOS-like mouse model was established via DHEA injection, and Hupcos overexpression was induced by AAV9, with estrous cycles, hormone levels, and ovarian histology examined. Mechanistic studies in KGN cells included overexpression and knockdown assays, immunoprecipitation, ubiquitination, and dual-luciferase reporter assays.</p><p><strong>Results: </strong>PCOS patients showed higher HUPCOS expression (p < 0.01) and testosterone levels (p < 0.0001), and reduced CYP19 A1 in granulosa cells. Hupcos-overexpressing mice showed PCOS-like symptoms, including estrous cycle disturbances and hormonal imbalances. In vitro, HUPCOS overexpression suppressed aromatase expression and estradiol production, while enhancing androstenedione accumulation. Mechanistically, HUPCOS promoted RBPMS ubiquitination, reduced its interaction with SMAD4, and downregulated CYP19 A1 transcription. Co-overexpression of RBPMS and HUPCOS reversed these effects.</p><p><strong>Conclusions: </strong>HUPCOS impairs estrogen biosynthesis in PCOS by enhancing RBPMS degradation and disrupting SMAD4-mediated transcription of CYP19 A1. These findings highlight a novel lncRNA-mediated mechanism contributing to hyperandrogenemia and follicular arrest, offering potential targets for PCOS therapy.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"105"},"PeriodicalIF":5.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144309588","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":"Single-cell spatial proteomics of non-relapse small cell lung cancer identifies tumor microenvironment determinants of survival.","authors":"Yin Li, Liliang Xia, Hui Wang, Xinghao Ai, Ying Wang, Qingquan Luo, Yuchen Han, Shun Lu, Xinghua Cheng","doi":"10.1007/s10565-025-10056-0","DOIUrl":"10.1007/s10565-025-10056-0","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is characterized by high malignancy and early propensity for metastasis, and modest response to immunotherapy due to the immunosuppressive microenvironment. Surgical intervention has shown benefits in treating early-stage SCLC. However, most patients experience recurrence after surgery. The factors associated with relapse free survival in these patients remain unclear. We collected operation specimens from ten early-stage SCLC patients (N0M0), conducted long-term follow-up, and grouped them based on disease status. Subsequently, we performed a retrospective analysis using single-cell spatial imaging mass cytometry to explore the characteristics of tumor cells and differences in the tumor microenvironment, especially the single-cell constitute of immune cells, between the two groups. We found that, in early-stage SCLC, tumor cells display pronounced heterogeneity, both intra-group and inter-group. Patients with early recurrence are characterized by a distinct subpopulation of tumor cells with high Ki-67 expression. Non-relapse patients demonstrate better infiltration of M1 macrophages and stromal cells. Neighborhood analysis suggested that positive interactions between macrophages, stromal cells, and T cells with tumor cells may benefit patient prognosis. Additionally, recurrent tumor cells might enhance their metastatic capacity and remodel the microenvironment through upregulation of GranzymeB or reduction of c-Myc expression. In conclusion, SCLC tumor cells demonstrate tumor heterogeneity and microenvironmental changes in the early clinical stages. A higher proportion of M1 macrophages is associated with prolonged postoperative survival in early-stage SCLC patients. This research provides novel insights and evidence for treating and preventing postoperative recurrence in SCLC.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"106"},"PeriodicalIF":5.3,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12174242/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144315963","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":"GelMA hydrogel-loaded extracellular vesicles derived from keratinocytes promote skin microvasculature regeneration and wound healing in diabetic mice through activation of the PDGF-induced PI3K/AKT pathway.","authors":"Qian Li, Leilei Zhou, Wenqiang Li, Weiheng Zhao, Weimin Chen, Mohammed S AlQranei, Jiarui Bi, Ping Huang","doi":"10.1007/s10565-025-10062-2","DOIUrl":"10.1007/s10565-025-10062-2","url":null,"abstract":"<p><strong>Objective: </strong>This study explores how extracellular vesicles (EVs) derived from keratinocytes cultured in Gelatin Methacryloyl (GelMA) hydrogels facilitate microvascular regeneration and enhance wound repair in diabetic skin ulcers.</p><p><strong>Methods: </strong>EVs were harvested from keratinocyte cultures via ultracentrifugation and ultrafiltration, followed by characterization. Their uptake and angiogenic effects on human umbilical vein endothelial cells (HUVECs) were assessed in the following experimentations. Transcriptomic profiling of EV-treated HUVECs identified angiogenesis-related gene expression changes. A diabetic murine wound model was established and validated via glycemic profiling and pancreatic histology. In vivo effects of GelMA-EVs were evaluated through wound closure rates, histology (re-epithelialization, vascularization, collagen deposition), CD31 staining, and microvascular imaging.</p><p><strong>Results: </strong>Keratinocyte-derived EVs significantly enhanced HUVEC proliferation, migration, and tube formation. Mechanistic studies reported elevated PDGF expression, activating the PI3K/AKT pathway. In vivo experiments validated that GelMA hydrogel-loaded EVs increased PDGF expression in wound tissues, promoting microvascular reconstruction and accelerating wound healing in diabetic mouse skin ulcers.</p><p><strong>Conclusion: </strong>GelMA hydrogel-loaded EVs derived from keratinocytes upregulate PDGF, activating the PI3K/AKT pathway to promote microvascular network reconstruction and enhance wound healing in diabetic mouse skin ulcers.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"103"},"PeriodicalIF":5.3,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12167351/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293373","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":"From neurotoxicity to neuroprotection: Rethinking GABA_AR-targeting anesthetics.","authors":"Yubao Li, Hongliang Yang, Lu Liu, Lulu Jiang, Peilin Xie, Xiaoling Wang, Xuhui Cong, Ruilou Zhu, Zhongyuan Lu, Mingyang Sun, Jiaqiang Zhang","doi":"10.1007/s10565-025-10057-z","DOIUrl":"10.1007/s10565-025-10057-z","url":null,"abstract":"<p><p>The brain growth spurt (BGS) represents a pivotal window in neurodevelopment, defined by rapid neurogenesis, heightened synaptogenesis, and the dynamic establishment of neural networks. During this phase, heightened brain plasticity significantly enhances learning and memory abilities, while also increasing the brain's susceptibility to disruptions. Anesthetics, particularly those targeting γ-aminobutyric acid type A receptors (GABA_ARs), interfere with GABAergic and glutamatergic systems, disrupt brain-derived neurotrophic factor (BDNF) signaling, and exacerbate neurotoxic effects. These agents activate glial cells, induce inflammation, and contribute to oxidative stress, while also disrupting calcium homeostasis and triggering endoplasmic reticulum stress. Furthermore, anesthetics alter the expression of non-coding RNAs, which affects gene regulation and long-term memory formation. The extent of neurotoxic effects is contingent upon a constellation of factors, including the timing, dosage, and frequency of anesthetic exposure, as well as individual susceptibility. Notably, perioperative administration of anesthetic agents has been implicated in long-term cognitive dysfunction, thereby emphasizing the critical importance of precisely modulated dosing regimens and temporally optimized delivery strategies to mitigate potential neurodevelopmental risks. In contrast, neuroactive steroids demonstrate promising neuroprotective potential by modulating GABA_AR activity, enhancing BDNF release, and regulating oxidative stress and inflammation. New strategies for preventing and reversing anesthetic-induced neurotoxicity could include novel anesthetic combinations, anti-apoptotic agents, antioxidants, or nutritional supplements. These findings underscore the complex and multifactorial effects of anesthetic agents on the developing brain and emphasize the urgent need to establish and refine anesthetic strategies that safeguard neural integrity during vulnerable windows of neurodevelopment.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"104"},"PeriodicalIF":5.3,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12167312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293372","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":"NFATC2/SERPINE1/JAK3/STAT3 signaling feedback loop in gastric cancer: immune evasion and anti-PD-1 resistance.","authors":"Zhenyu Yang, Dingwen Zhong, Xi'e Hu, Wenhui Chen, Yonghui Liao, Xianli He","doi":"10.1007/s10565-025-10050-6","DOIUrl":"10.1007/s10565-025-10050-6","url":null,"abstract":"<p><strong>Objectives: </strong>This research investigates how the SERPINE1-associated tumor microenvironment influences anti-PD-1 treatment response in gastric carcinoma (GC).</p><p><strong>Methods: </strong>Bioinformatics analysis, cellular experiments, and animal models were employed to quantify the levels of NFATC2, SERPINE1, JAK3, STAT3, and to explore their associations with various biological behaviors of GC cells, encompassing proliferation, migration, invasiveness, EMT, and immune cell infiltration. Additionally, by constructing a GC tumor-bearing model, we assessed the efficacy of knocking down SERPINE1 in combination with anti-PD-1 therapy.</p><p><strong>Results: </strong>Elevated SERPINE1 expression in GC correlated with enhanced tumor aggressiveness, lymphatic dissemination, and adverse prognostic indicators. NFATC2, a potential transcription factor of SERPINE1, showed high expression that correlated with poor prognosis in GC patients. NFATC2 orchestrates JAK3/STAT3 pathway activation via SERPINE1 induction, culminating in STAT3 upregulation. Concurrently, STAT3 regulates the upregulation of NFATC2, which in turn further enhances SERPINE1 levels, establishing a positive feedback loop. This loop facilitates the proliferation, clonogenic growth, migration, invasion, and EMT processes of GC cells, thereby accelerating the progression of GC. Additionally, the NFATC2/SERPINE1 axis may facilitate immune evasion in GC by increasing the presence of PD-L1⁺ M2 macrophages. Importantly, silencing SERPINE1 enhanced the sensitivity of GC xenografts to anti-PD-1 therapy.</p><p><strong>Conclusion: </strong>Our study reveals the critical function of the NFATC2/SERPINE1/JAK3/STAT3 positive feedback loop in gastric carcinogenesis while identifying its plausible contribution to anti-PD-1 therapy resistance mechanisms.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"102"},"PeriodicalIF":5.3,"publicationDate":"2025-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12166020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282461","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":"Oral squamous cell carcinoma: Insights into cellular heterogeneity, drug resistance, and evolutionary trajectories.","authors":"Yang Zhou, Liyin Wang, Minghua Liu, Hongfang Jiang, Yan Wu","doi":"10.1007/s10565-025-10048-0","DOIUrl":"10.1007/s10565-025-10048-0","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) can lead to metastasis and high mortality rates known for its aggressive and invasive properties. Currently, primary treatment options of surgical resection, chemotherapy and radiotherapy have many therapeutic limitations for OSCC patients due to its dynamic evolutionary pathways and the development of resistance to conventional therapies. Moreover, previous studies fail to emphasize the roles of cellular heterogeneity, drug resistance, and evolutionary trajectories in OSCC. This review explores the intricate tumor microenvironment landscape of OSCC, focusing on the cellular heterogeneity, drug resistance, and evolutionary trajectories as well as genetic, epigenetic, and environmental risk factors contributing to the OSCC progression. Tumor heterogeneity arises from environmental exposures (e.g., tobacco, HPV infection, dietary carcinogens) that drive clonal evolution, creating subpopulations of cells with distinct mutational profiles and therapeutic vulnerabilities. Recent advances in in the precision medicine and combination therapy of OSCC paves the way for innovative therapeutic strategies, such as targeting molecular subclones through real-time monitoring and leveraging computational models to predict treatment response. By recognizing tumor heterogeneity as both a driver of therapeutic resistance and a therapeutic target, precision medicine frameworks can integrate environmental risk factor data, molecular profiling, and early detection tools to optimize outcomes. This review underscores the necessity for a multidisciplinary approach to understand and combat the complexity of OSCC, proposing directions for future research to enhance diagnosis and treatment efficacy.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"101"},"PeriodicalIF":5.3,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274269","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":"Correction to: Statins induce skeletal muscle atrophy via GGPP depletion-dependent myostatin overexpression in skeletal muscle and brown adipose tissue.","authors":"Lai Wang, Zu-Guo Zheng, Lingchang Meng, Lijun Zhu, Ping Li, Jun Chen, Hua Yang","doi":"10.1007/s10565-025-10059-x","DOIUrl":"10.1007/s10565-025-10059-x","url":null,"abstract":"","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"98"},"PeriodicalIF":5.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12148982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144257432","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":"Dissecting the METTL3/STC2 axis in colorectal cancer: implications for drug resistance and metastasis.","authors":"Qiang Su, Kaiyue Wang, Ruohan Liao, Hanyu Zhang, Bochu Wang","doi":"10.1007/s10565-025-10043-5","DOIUrl":"10.1007/s10565-025-10043-5","url":null,"abstract":"<p><p>In recent years, the role of epigenetic modifications, especially N6-methyladenosine (m6A) modifications, in the occurrence and development of cancer has received increasing attention. This study aims to elucidate the role of m6A modification in colorectal cancer (CRC), focusing on the effect of METTL3 on STC2 expression and its effects on cell proliferation, drug resistance and metastasis. Using MeRIP-seq, mRNA-seq, EdU staining, CCK-8 (Cell Counting Kit-8) assay, Transwell assay, Western blot and flow cytometry, this study confirmed that RNA methylation was predominantly located in the CDS region and that STC2 was overexpressed in advanced cancer and 5-FU (5-Fluorouracil)-resistant cell lines. Knockdown of STC2 increased the sensitivity of cells to 5-FU, reduced cell proliferation and metastatic capacity, and indicated that METTL3 positively regulates STC2 m6A modification. Further experiments showed that METTL3 knockdown reduced the IC50 (Half Maximal Inhibitory Concentration) of 5-FU-resistant CRC cells, inhibited cell proliferation, ERS (Endoplasmic Reticulum Stress) and oxidative stress, and reduced KRAS G12 and G13 mutations, and these effects were reversed by STC2 overexpression. In vivo, METTL3 knockdown enhanced the efficacy of 5-FU and inhibited tumor metastasis, whereas STC2 overexpression counterbalanced these benefits. Overall, our findings suggest the METTL3/STC2 axis as a promising therapeutic target to combat drug resistance and metastasis in colorectal cancer.</p>","PeriodicalId":9672,"journal":{"name":"Cell Biology and Toxicology","volume":"41 1","pages":"100"},"PeriodicalIF":5.3,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12152045/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265330","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}