International Journal of Biological Sciences最新文献

{"title":"Epithelial DPP4 promotes Ang II-driven renal fibrosis by targeting ACE2 activity in the renin-angiotensin system.","authors":"Yingying Zhang, Ruizhi Tan, Lehao Wu, Dan Zhao, Cheng Zhong, Chenggong Luo, Jeff Yat-Fai Chung, Patrick Ming-Kuen Tang, Chen Yu","doi":"10.7150/ijbs.106418","DOIUrl":"10.7150/ijbs.106418","url":null,"abstract":"<p><p>Renal fibrosis is a characteristic of the progression of various chronic kidney diseases (CKD) to end-stage renal disease (ESRD). The renin-angiotensin system (RAS) is key to renal pathology. A better understanding of its regulatory mechanisms at the molecular level may lead to solutions for clinical CKD. Interestingly, our cohort study observed a positive correlation between epithelial dipeptidyl peptidase-IV (DPP4) levels and clinical CKD progression. Consistently, DPP4 was significantly increased in the unilateral ureteral obstruction (UUO) injured kidney <i>in vivo</i> and human epithelial kidney HK-2 cells under Ang II stimulation <i>in vitro</i>. Unexpectedly, kidney-specific deletion of DPP4 effectively ameliorated UUO and ischemia/reperfusion (I/R)-driven renal fibrosis <i>in vivo</i>. Mechanistically, we reveal that DPP4 serves as a novel inhibitor of the Ang(1-7)/MasR axis and an inducer of the AT1R axis by directly binding to ACE2 at the protein level. More importantly, targeting DPP4 with pharmaceutical inhibitor linagliptin effectively restored anti-fibrotic pathway of RAS, thereby blocking the CKD progression of I/R-injured kidney <i>in vivo</i>. Therefore, epithelial DPP4 may represent a precise therapeutic target to enhance the anti-fibrotic activity of RAS for CKD treatment in the clinic.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"3901-3916"},"PeriodicalIF":8.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210238/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Arsenic disrupts H3K9me3 and H3K27me3 balance by biasing PRC2.1 and PRC2.2 activity via PALI1 inhibition in carcinogenesis.","authors":"Haoyan Ji, Millie Elangbam, Yiran Qiu, Jessica Bamrah, Wenxuan Zhang, Aashna Pawar, Chitra Thakur, Fei Chen, Ziwei Wang","doi":"10.7150/ijbs.115605","DOIUrl":"10.7150/ijbs.115605","url":null,"abstract":"<p><p>Inorganic arsenic (As³⁺) is a well-established human carcinogen, yet the molecular mechanisms underlying its oncogenic potential remain incompletely understood. Here, we show that exposure to environmentally relevant concentrations of As³⁺ disrupts chromatin architectures in human bronchial epithelial cells (BEAS-2B) by discordantly regulating two key repressive histone modifications: histone H3 lysine 27 trimethylation (H3K27me3) and H3K9me3. Chromatin immunoprecipitation and sequencing (ChIP-seq) reveals a genome-wide gain of H3K27me3 and a marked loss of H3K9me3 following As³⁺ treatment. Mechanistically, As³⁺ downregulates PALI1, an essential accessory subunit of the polycomb repressive complex 2.1 (PRC2.1), which uniquely coordinates H3K27me3 and H3K9me3 deposition via EZH2 and G9a, respectively. Loss of PALI1 impairs this dual repression mechanism, leading to widespread chromatin deregulation. Gene ontological analysis reveals that regions with diminished H3K9me3 in As³⁺-treated cells are enriched in pathways related to PRC2 activity, ribosomal biogenesis, stemness-associated transcription factors, xenobiotic metabolism (phases I and II), and GPCR signaling. Notably, these regions also include LINE-1 retrotransposons, whose de-repression is known to drive genomic instability-a hallmark of cancer. Given PALI1's potential tumor-suppressive role in lung, breast, and colon cancers, and other malignancies, its suppression by As³⁺ likely contributes to carcinogenesis through epigenetic reprogramming, genome destabilization, and activation of oncogenic transcriptional programs. These findings reveal a novel mechanism of As³⁺-induced epigenetic dysregulation and highlight the central role of histone modifications in environmental carcinogenesis.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"4069-4080"},"PeriodicalIF":8.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144559969","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deubiquitinating enzymes: Key regulators of ferroptosis and pyroptosis and novel targets for cancer intervention.","authors":"Sheng-Kai Hsu, I-Ying Kuo, Pin-Yuan Lin, Chon-Kit Chou, Ching-Chung Ko, Wen-Tsan Chang, Chien-Chih Chiu","doi":"10.7150/ijbs.111867","DOIUrl":"10.7150/ijbs.111867","url":null,"abstract":"<p><p>Most chemotherapeutic drugs are introduced to eliminate tumors by targeting apoptotic cell death, but chemoresistance frequently develops owing to the aberrant apoptotic machinery. Although the emergence of immune checkpoint blockade (ICB) has revolutionized cancer therapeutics, poor responses to ICB and an immunosuppressive tumor microenvironment are commonly observed in solid tumors. Hence, restoring chemosensitivity and immunosurveillance is important for improving patient outcomes. Recently, the induction of nonapoptotic programmed cell death (PCD), such as ferroptosis and pyroptosis, has received much attention since these alternative forms of cell death potentially increase chemosensitivity and augment antitumor immunity. Ubiquitination and deubiquitination are well-recognized posttranslational modifications, and the balance between these processes is important for maintaining cellular homeostasis. Dysregulation of deubiquitinating enzymes (DUBs) is reportedly associated with tumor progression. Additionally, emerging studies have suggested the involvement of DUBs in modulating cellular susceptibility to nonapoptotic PCD. Nevertheless, the crosstalk between DUBs and nonapoptotic PCDs and their implications for cancer treatment have not been thoroughly reviewed. In this review, we elucidate the roles of DUBs in regulating ferroptosis and pyroptosis via their DUB activities or noncanonical functions. Moreover, we thoroughly discuss the challenges and urgent problems associated with targeting DUBs to induce nonapoptotic PCDs as cancer therapeutics.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"3993-4009"},"PeriodicalIF":8.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unlocking the Puzzle of Mammalian Transfection: The Role of the RNA-sensing-Mediated Interferon Response in the Cellular Defense Against Foreign DNA Intrusion.","authors":"Xiaoyu Li, Yicen Zhou, Jie Wei, Wei Sun, Ligang Fan, Jian Yan","doi":"10.7150/ijbs.107510","DOIUrl":"10.7150/ijbs.107510","url":null,"abstract":"<p><p>The introduction of foreign DNA into mammalian cells to express a given gene or genes of interest is a pivotal process with significant implications for molecular biology and gene therapy. Despite the development of various methods to improve transfection efficiency, it remains suboptimal in many cell types. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) senses transfected DNA and elicits an innate immune response, leading to low transfection efficiency. However, the mechanism by which transgene expression is repressed by cGAS-STING activation remains elusive. In this study, we demonstrated the crucial involvement of multiple RNA processing pathways under the control of cGAS-STING-activated IRF3/7 in suppressing transgene expression. These pathways included RNA-sensing genes (e.g., MDA5 and RIGI), as well as the OAS family (mRNA degradation) and the IFIT family (translation inhibition). By depleting IRF3/7, cGAS-STING, or RNA-sensing genes, we observed a significant increase in the transfection efficiency of the treated cells, with the most pronounced effects observed in the STING and MDA5 double-knockdown group. Our findings provide insights into the interconnected roles of DNA- and RNA-sensing mechanisms in innate immune activation triggered by transgene expression, thereby suggesting potential strategies to increase transfection efficiency in biomedical research.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"3886-3900"},"PeriodicalIF":8.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12210383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-cohort validation of a lipid metabolism and ferroptosis-associated index for prognosis and immunotherapy response prediction in hormone receptor-positive breast cancer.","authors":"Cheng Zeng, Jiani Wang, Shen Zhao, Yuhan Wei, Yalong Qi, Shuning Liu, Yuanyi Wang, Hewei Ge, Xiaoqi Yang, Yujing Tan, Yizhou Jiang, Haili Qian, Fei Ma","doi":"10.7150/ijbs.113213","DOIUrl":"10.7150/ijbs.113213","url":null,"abstract":"<p><p><b>Background:</b> Hormone receptor-positive (HR+) breast cancer exhibits significant heterogeneity influenced by lipid metabolism and ferroptosis (LMF). While immune checkpoint inhibitors have shown promise in neoadjuvant therapy, as evidenced by the KEYNOTE-756 and CheckMate 7FL trials, identifying the optimal patient population remains challenging. This study aims to classify molecular clusters based on LMF-related genes and develop the LMF_index to predict prognosis and immunotherapy response in HR+ breast cancer. <b>Methods:</b> Transcriptome and clinical data of HR+ breast cancer were obtained from the Cancer Genome Atlas and Gene Expression Omnibus databases. Unsupervised clustering based on prognostic LMF-related genes identified molecular clusters, followed by tumor mutational burden (TMB) and immune microenvironment (TME) analysis. The LMF_index was constructed using least absolute shrinkage and selection operator and multivariate Cox regression analyses and validated across multiple internal and external cohorts. Its predictive value for neoadjuvant immunotherapy efficacy was assessed using GSE173839. Validation at the transcriptomic level was conducted in the Shanghai cohort, while protein-level validation was performed using multiplex immunohistochemistry (mIHC) on a tissue microarray comprising 113 breast cancer samples. Spatial analyses further examined the distribution of key panel genes within the TME. <b>Results:</b> Two molecular clusters were identified in this study. Cluster 1 exhibited higher TMB, tumor purity, and Ki-67, while Cluster 2 showed greater CD8+ T cells and elevated PD-1, PD-L1, and CTLA4 expression. The LMF_index, derived from a seven-gene panel (KRT5, CD209, KLRB1, MRC1, UGT2B4, FABP7, and BIRC3), effectively stratified patients into high and low LMF_index groups, with high LMF_index patients showing significantly shorter overall survival. Patients with a low LMF_index demonstrated elevated ACSL4 expression, enhanced immune activity, higher immunophenoscores, and increased pathological complete response rates following neoadjuvant immunotherapy, indicating a greater potential benefit from immunotherapy. The prognostic value of the LMF_index was validated at the transcriptomic level in the Shanghai cohort and at the protein level using mIHC on a tissue microarray. Spatial analysis further demonstrated KLRB1 enrichment in the tumor stroma, correlating with CD8+ T cell and M1 macrophage infiltration, and an enhanced response to immunotherapy. <b>Conclusions:</b> This study identified distinct LMF-related molecular clusters in HR+ breast cancer with unique prognostic and immune characteristics. The LMF_index shows potential as a prognostic biomarker and a guide for immunotherapy strategies in HR+ breast cancer.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"3968-3992"},"PeriodicalIF":8.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"WNT5B regulates myogenesis and fiber type conversion by affecting mRNA stability.","authors":"Danyang Fan, Yilong Yao, Chao Yan, Fanqinyu Li, Yalan Yang, Bingkun Xie, Zhonglin Tang","doi":"10.7150/ijbs.102309","DOIUrl":"10.7150/ijbs.102309","url":null,"abstract":"<p><p>The wingless-integrated (WNT) signaling pathway is known to play a critical role in myogenesis. <i>WNT5B</i>, a member of the WNT family, is essential for determining cell fate and development. However, the molecular mechanisms by which <i>WNT5B</i> regulates myogenesis remain unclear. This study observed that <i>WNT5B</i>, which is conserved between mice and pigs, is highly expressed in the skeletal muscle. The expression of <i>WNT5B</i> was varied in the skeletal muscle between the Tongcheng (obese-type) and Landrace (lean-type) pigs. <i>In vitro</i>, <i>WNT5B</i> promoted skeletal muscle cell proliferation and cell cycle progression, while inhibited cell apoptosis. <i>In vivo</i>, <i>WNT5B</i> promoted myofiber thickness and increased slow-type muscle fibers in porcine skeletal muscles. Mechanically, a SNP site (c.1608 A > G) located in the 3' untranslated region (3'UTR) of <i>WNT5B</i> regulated transcript attenuation and acts through AU-rich element mediation (ARE) to influence myogenesis. Also, the SNP was located in the miRNA response element of miR-29a/b/c to influence <i>WNT5B</i> expression. However, ARE sites did not affect the binding relationship of miR-29a/b/c. In conclusion, this study demonstrated that the SNP (c.1608 A > G) affects <i>WNT5B</i> mRNA stability by protecting the 3'UTR of the <i>WNT5B</i> from the degrading effects of miR-29a/b/c. This study reveals the critical role of <i>WNT5B</i> in myogenesis and indicates that it is a novel candidate gene for pig breeding.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 9","pages":"3934-3948"},"PeriodicalIF":8.2,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12223781/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560078","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Erratum: The inhibition of YTHDF3/m⁶A/LRP6 reprograms fatty acid metabolism and suppresses lymph node metastasis in cervical cancer: Erratum.","authors":"Sheng Zhong, Quanwei Guo, Xiaona Chen, Xiaomin Luo, Yufei Long, Tuotuo Chong, Ming Ye, Hui He, Anwei Lu, Keyi Ao, Minuo Yin, Aimin Xu, Xin Li, Yi Hao, Xia Guo","doi":"10.7150/ijbs.115928","DOIUrl":"https://doi.org/10.7150/ijbs.115928","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.7150/ijbs.87203.].</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3825-3826"},"PeriodicalIF":8.2,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160856/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomes: a promising microenvironment modulator for spinal cord injury treatment.","authors":"Yanming Ma, Xiaojun Yu, Jingxin Pan, Yingguang Wang, Ruoyu Li, Xiaodong Wang, Huimin Hu, Dingjun Hao","doi":"10.7150/ijbs.115242","DOIUrl":"10.7150/ijbs.115242","url":null,"abstract":"<p><p>Spinal cord injury (SCI) remains a severely disabling disorder that impacts millions globally by causing irreversible damage to the nervous system. Although cell - based therapies have shown notable progress, the post - injury microenvironment presents significant obstacles that hinder the survival and effectiveness of implanted cells, ultimately limiting sustained functional restoration. Exosomes have emerged as a promising cell - free therapeutic alternative due to their stability, low immunogenicity, and ability to carry bioactive molecules such as proteins, microRNAs, and lipids. These vesicles can modulate the injured microenvironment, support neuroprotection, and facilitate repair. This review begins by discussing the pathological alterations that disrupt the microenvironment following SCI. The review then outlines the process of exosome formation and highlights their structural features. Furthermore, the review delves into the diverse cellular sources of exosomes and evaluates their therapeutic relevance in the context of SCI. Special attention is given to the multifaceted roles exosomes play in neuroprotection, such as reinforcing the blood - spinal cord barrier, stimulating axonal regeneration, promoting new blood vessel formation, suppressing programmed cell death in neurons, and modulating inflammatory responses. The synergistic use of exosomes in combination with biomaterials is also explored, with the aim of optimizing their therapeutic potential. Lastly, the review addresses the key obstacles that must be overcome to bring exosome - based treatments into clinical application and offers perspectives on future advancements in this evolving field. In summary, exosomes offer a novel and promising avenue for SCI intervention, holding considerable promise as an alternative to traditional therapeutic approaches.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3791-3824"},"PeriodicalIF":8.2,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cyclophilin J Reprograms Tumor-associated Macrophages to Exert an Anti-tumor Effect in Liver Cancer.","authors":"Jing Wang, Chen Yao, Qi Zeng, Lixia Peng, Shimeng Zhang, Yizhi Mao, Lingyi Fu, Shuai Chen, Chunjie Sheng","doi":"10.7150/ijbs.113197","DOIUrl":"10.7150/ijbs.113197","url":null,"abstract":"<p><p>The presence of tumor-associated macrophages (TAMs) characterized by an M2-like phenotype sustains a robust immunosuppressive tumor microenvironment (TME), promoting liver hepatocellular carcinoma (LIHC) progression. Here, we find that genetic deletion of cyclophilin J (CYPJ) in mice significantly accelerates the development of liver cancer. Analysis of immune cell infiltration reveals that high expression of CYPJ correlates with an increased proportion of M1-polarized, anti-tumor macrophages and CD8⁺ T cells in the TME. Mechanistically, we demonstrate that CYPJ interacts with AKT1 and inhibits the PI3K-AKT signaling pathway, which leads to polarization of TAMs toward the anti-tumor M1 phenotype, resulting in a tumor-suppressive effect. Collectively, our findings implicate CYPJ as a novel potential therapeutic target for macrophage-mediated therapy in liver cancer.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3776-3790"},"PeriodicalIF":8.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144302008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"METTL3 mediated m6A modification of HKDC1 promotes renal injury and inflammation in lead nephropathy.","authors":"Xiao-Guo Suo, Jia-Nan Wang, Qi Zhu, Meng-Meng Zhang, Qing-Lin Ge, Li-Jin Peng, Yue-Yue Wang, Ming-Lu Ji, Yang-Mei Ou, Ju-Tao Yu, Hao Lu, Xin-Ran Cheng, Bing-Bing Hou, Xin Chen, Sai Zhu, Xiang-Yu Li, Chao Li, Shuai-Shuai Xie, Chen Yang, Feng-He Li, Juan Jin, Fang Wang, Xiao-Ming Meng","doi":"10.7150/ijbs.112463","DOIUrl":"10.7150/ijbs.112463","url":null,"abstract":"<p><p>Environmental and industrial Pb exposure poses a significant public health challenge. Acute exposure to high Pb concentrations can result in renal injury. Here, we revealed that N6-methyladenosine (m6A) RNA methylation was significantly upregulated in lead nephropathy and was mainly mediated by the methyltransferase METTL3. Functionally, METTL3 knockout in renal tubular epithelial cells or AAV9-mediated METTL3 silencing alleviated renal injury and the inflammatory response induced by lead acetate. METTL3 silencing in renal tubular epithelial cells reduced both m6A RNA methylation and inflammatory responses following lead acetate treatment. We identified hexokinase domain-containing 1 (HKDC1), known to function in the glycolytic pathway, as a direct METTL3 target. Importantly, HKDC1 was upregulated at both mRNA and protein levels after lead acetate treatment, thereby promoting renal injury and inflammation. Mechanistically, HKDC1 binds to ATPB and antagonizes the ubiquitinase Murf1, thereby leading to increased expression of ATPB and activation of the NF-κB signaling pathway, which promotes renal inflammation. We further confirmed that STM2457, an inhibitor of METTL3, protected against renal injury and inflammation induced by lead acetate. Collectively, our study demonstrated that the METTL3/HKDC1 axis is a potential target for the treatment of lead nephropathy, and STM2457 is expected to be a protective agent against renal injury caused by lead acetate.</p>","PeriodicalId":13762,"journal":{"name":"International Journal of Biological Sciences","volume":"21 8","pages":"3755-3775"},"PeriodicalIF":8.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12160926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144301941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}