Cell Death & Disease最新文献

{"title":"Correction: Modulation of oxidative phosphorylation augments antineoplastic activity of mitotic aurora kinase inhibition.","authors":"Zijian Zhang, Deshun Zeng, Wei Zhang, Ailin Chen, Jie Lei, Fang Liu, Bing Deng, Junxiao Zhuo, Bin He, Min Yan, Xinxing Lei, Shulan Wang, Eric W-F Lam, Quentin Liu, Zifeng Wang","doi":"10.1038/s41419-025-07968-4","DOIUrl":"10.1038/s41419-025-07968-4","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"719"},"PeriodicalIF":9.6,"publicationDate":"2025-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12511391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145257419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cut the fat: targeting cholesterol and lipid metabolism in glioblastoma.","authors":"Safet Zekanovic, Puspha Achaiber Sing, Sieger Leenstra, Martine L M Lamfers","doi":"10.1038/s41419-025-07993-3","DOIUrl":"10.1038/s41419-025-07993-3","url":null,"abstract":"<p><p>In the past decades, much research has been focused on identifying oncogenic signaling events in glioblastoma (GBM). Based on these findings, novel therapeutics have been extensively tested in clinical trials. These include targeted agents (e.g., kinase inhibitors), anti-angiogenic drugs, and immunotherapies. Unfortunately, no survival benefit has been demonstrated with the use of these agents. The lack of efficacy observed in the past decades poses the question of whether we are targeting the right pathways to halt the growth of GBM. In this review article, we discuss the intricacies of cholesterol and lipid metabolism in GBM. We provide an overview of which oncogenic signaling pathways are fueled by the aberrant cholesterol and lipid metabolism in GBM. Importantly, we also discuss how metabolic rewiring in the context of cholesterol and lipids can contribute to immune evasion in GBM. Lastly, we provide an overview of current drugs targeting cholesterol and fatty acid metabolism and their potential to serve as targeted therapies for GBM.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"717"},"PeriodicalIF":9.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504701/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243895","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dynamic role of TRIM8, a novel ciliary protein, during various stages of mitosis.","authors":"Utsa Bhaduri, Eleonora Di Venere, Gabriella Maria Squeo, Giorgia Gemma, Francesco Tamiro, Rosario Avolio, Emanuela Senatore, Lucia Salvemini, Rosa Di Paola, Danilo Licastro, Ilaria Iacobucci, Valentina Tretola, Paolo Salerno, Antonio Feliciello, Maria Monti, Vincenzo Giambra, Giuseppe Merla","doi":"10.1038/s41419-025-07973-7","DOIUrl":"10.1038/s41419-025-07973-7","url":null,"abstract":"<p><p>TRIM8 is an E3 ubiquitin ligase that functions as both a tumour suppressor and an oncoprotein. Earlier, we reported that TRIM8 interacts with key regulators of mitotic spindle assembly, and that TRIM8 knockdown results in mitotic delay and aneuploidy. In this study, we implemented an omics strategy with differential transcriptomic (single-cell RNA sequencing or scRNA-seq), translatomic (polysome profiling with RNA-seq), and proteomic (LC-MS/MS) approaches to elucidate the involvement of TRIM8 in different levels (transcription, translation, post-translation) and stages (G0/G1, S, G2/M) of mitotic cell cycle regulation and progression. With the aid of differential transcriptomic and proteomic approaches, we show that depletion of TRIM8 perturbs the canonical 'Cell Cycle Control of Chromosomal Replication' pathway. Furthermore, TRIM8 downregulation induces alterations in the translation activity of cells and results in the upregulation of polysome-bound MALAT1 lncRNA by means of significant changes in polysome profiling coupled with RNA-sequencing. Moreover, we unveil for the first time endogenous TRIM8 as a novel ciliary protein that localizes with CEP170 at centrosome. Cilia analysis revealed a significant reduction in the number of ciliated cells, along with shorter cilia, in TRIM8-silenced ARPE-19 cells. Our study is the first to demonstrate the dynamic role of a TRIM family protein across multiple stages of mitosis and to define TRIM8 as a novel ciliary protein.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"707"},"PeriodicalIF":9.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E3 Ubiquitin ligases Cbl-b and c-Cbl maintain the homeostasis of macrophages by regulating the M-CSF/M-CSFR signaling axis.","authors":"Fei Xu, Chensheng Tan, Kun Tang, Guodong Qiao, Yu Shao, Xiaoping Li, Ji Zhou, Peijie Zhu, Mengyun Wu, Jiamin Cai, Xiu Gao, Yufeng Wang, Beibei Huang, Wenjun Wang, Tian Xia, Xuena Xu, Jiaoyang Li, Zhengrong Chen, Yufang Shi, Chuangli Hao, Yi Yang, Jinping Zhang","doi":"10.1038/s41419-025-08047-4","DOIUrl":"10.1038/s41419-025-08047-4","url":null,"abstract":"<p><p>The Casitas B-lineage lymphoma (Cbl) family proteins are E3 ubiquitin ligases implicated in the regulation of various immune cells. However, their function in macrophages remains unclear. Here, we identify both Cbl-b and c-Cbl (Cbls) as inhibitors of macrophage proliferation and promoters of macrophage apoptosis. Mechanically, we identify that Cbls functions upstream of AKT and Erk to mediate the ubiquitination and degradation of M-CSFR. M-CSF stimulation promotes dimerization and autophosphorylation activation of M-CSFR on the macrophage membrane, thereby activating downstream PI3K-AKT and Erk signaling pathways, leading to different biological effects such as macrophage proliferation and survival. At the same time, the Y559 site of the M-CSFR undergoes autophosphorylation, which can promote receptor recruitment and phosphorylation of Cbls. This promotes Cbls to induce K63-linked polyubiquitination at the K791 site of M-CSFR, leading to internalization and degradation of M-CSFR through lysosomal pathways, preventing excessive activation of the signaling pathway. Furthermore, Cbls deficiency results in increased proliferation and decreased apoptosis of macrophages in vitro and in vivo and dKO mice spontaneously develop a macrophage-dominated pulmonary enlargement. Together, these data demonstrate that Cbls play critical roles in the regulation of macrophage homeostasis by inhibiting M-CSFR-mediated AKT and Erk activation.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"716"},"PeriodicalIF":9.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deletion of C3G in hepatocytes impairs full liver maturation and alters glucose homeostasis.","authors":"Nerea Palao, Jaime Mancebo, Cristina Baquero, Minerva Iniesta-González, Mateo Cueto-Remacha, María Rodrigo-Faus, Alvaro Gutierrez-Uzquiza, Paloma Bragado, Ángel M Cuesta, Aránzazu Sánchez, Carmen Guerrero, Almudena Porras","doi":"10.1038/s41419-025-08031-y","DOIUrl":"10.1038/s41419-025-08031-y","url":null,"abstract":"<p><p>C3G (RapGEF1) regulates the biology of liver hepatic progenitor cells and hepatocarcinoma cells, but its role in hepatocytes remained unknown. Therefore, we generated a mouse model lacking C3G in hepatocytes (C3GKO^Alb), which showed liver damage as evidenced by increased fibrosis, liver macrophages and serum transaminases activity. Furthermore, impaired liver maturation was observed in C3GKO^Alb mice demonstrated by the low expression of hepatocyte specific proteins (i.e. HNF4α), but higher levels of Alpha-fetoprotein, and stemness markers (i.e. CD133). Glucose homeostasis was also altered in C3GKO^Alb mice, as well as insulin and glucagon effects on hepatocytes, which resulted in reduced serum glucose levels and an enhanced response to glucagon. In addition, the expression of several glycolytic and gluconeogenic enzymes, as well as the levels of the active form of Glycogen phosphorylase (PYGL), were upregulated in livers from C3GKO^Alb mice, being remarkable the increased Pyruvate kinase isoform 2 (PKM2) levels accompanied by higher serum lactate concentrations. An increased expression of the ketogenic enzyme 3-hydroxy 3-methylglutaryl-CoA (HMG) synthase (Hmgcs2) was also found in these livers in parallel to elevated blood levels of beta-hydroxy-butyrate. Moreover, the fasting response was enhanced in C3GKO^Alb mice as compared to wt animals. Hence, livers lacking C3G in hepatocytes showed a higher expression of gluconeogenic, lipogenic and ketogenic enzymes than livers from wt mice and enhanced ketogenesis. Mechanistically, data support a PTBP1-mediated upregulation of PKM2 expression in hepatocytes lacking C3G, which leads to enhanced glycolysis. Other metabolic alterations are likely due to the defective insulin signaling and the enhanced glucagon signaling through a cAMP-PKA-dependent mechanism. In summary, we have identified a novel role for C3G in the liver as a key mediator of hepatocyte differentiation and metabolic functions of hepatocytes. Hence, its absence leads to an immature phenotype and an altered response to insulin and glucagon, favoring glucagon actions.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"711"},"PeriodicalIF":9.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504625/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms and targeted prevention of abnormal ductular reaction caused by a low concentration of Benzo(a)pyrene.","authors":"Xinru Du, Yancheng Gao, Sisi Song, Qinming Hui, Zhendong Wang, Mengyue Ji, Maoxuan Li, Shuoke Duan, Sha Liu, Ziyi Wang, Yue Ma, Ye Yang, Chunxiao Zhou, Yuan Li","doi":"10.1038/s41419-025-08043-8","DOIUrl":"10.1038/s41419-025-08043-8","url":null,"abstract":"<p><p>The impact of long-term exposure to low concentrations of environmental pollutants on hepatobiliary diseases is a major public health issue. Benzo(a)pyrene (B[a]P) is a common environmental toxin classified by the International Agency for Research on Cancer as a Group I carcinogen. Abnormal ductular reaction (DR) is a major pathological feature of hepatobiliary diseases; however, the underlying molecular mechanisms of B[a]P-induced abnormal DR remain unclear. This study revealed that chronic exposure to a low concentration of B[a]P increased the expression of a glucose-regulated protein (GRP75) in cholangiocytes. As GRP75 is a bridge protein for the endoplasmic reticulum (ER)-mitochondrial junction, the overexpression of GRP75 abnormalizes ER-mitochondria coupling. These biological processes facilitated Ca²⁺ release from the ER into the mitochondria and caused mitochondrial Ca²⁺ overload, leading to the overproduction of reactive oxygen species (ROS). The increased ROS activates epithelial-mesenchymal transition (EMT) and ultimately induces a profibrotic phenotype in bile duct cells (BECs). These cells secreted collagen and activated hepatic stellate cells through paracrine activity, which synergistically promoted the development and progression of fibrosis. Finally, via drug screening and functional analysis, we innovatively revealed a traditional Chinese medicine monomer, luteolin, which could prevent B[a]P-induced abnormal DR and hepatic fibrosis by targeting GRP75. Our study offers new insights into environmental toxin-induced hepatobiliary diseases and suggests a potential key interventional target or approach for the prevention of abnormal DR.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"714"},"PeriodicalIF":9.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504665/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SARS-CoV-2 delta and omicron variants alter trophoblast cell fusion and syncytiotrophoblast dynamics: new insights into placental vulnerability.","authors":"Manel Essaidi-Laziosi, Catia Alvarez, Michal Yaron, Pascale Sattonnet-Roche, Kenneth Adea, Mélanie Cornut, Christine Wuillemin, Meriem Bekliz, Yoann Sarmiento, Chloe Gibson, Laurent Kaiser, Anne-Laure Rougemont, Isabella Eckerle, Marie Cohen","doi":"10.1038/s41419-025-08016-x","DOIUrl":"10.1038/s41419-025-08016-x","url":null,"abstract":"<p><p>Pregnancy is associated with an increased risk of severe COVID-19. In addition, SARS-CoV-2 infection during gestation has been linked to adverse obstetrical outcomes and placental abnormalities. Nevertheless, the susceptibility of early trophoblast cells to SARS-CoV-2 and the potential consequences of infection on trophoblast function remain unclear. In this study, we assessed the permissiveness of first trimester trophoblast cells to SARS-CoV-2 infection and its impact on trophoblast cells fusion. To address this, we isolated primary cytotrophoblast (CTB) cells from first trimester human placentas and allow their differentiation into STB in vitro. These cells were infected with SARS-CoV-2 variants of concern, including Delta and Omicron (BA.1, BA.2, BA.5). Viral replication was assessed by RT-qPCR and immunofluorescence, while host cell responses, including expression of viral entry receptors and innate immunity genes, were measured by RT-qPCR. Trophoblast fusion was evaluated by staining and calculating the fusion index. In parallel, placental tissues from SARS-CoV-2-infected pregnancies were analyzed by immunohistochemistry to quantify syncytial knots (SK) formation in vivo. Our results demonstrate that both first trimester CTB and STB are permissive to SARS-CoV-2 infection in a variant- and donor-dependent manners, with Delta exhibiting higher replication efficiency compared to Omicron variants. In STB, viral replication did not correlate with the induction of entry receptors or type III interferon responses. However, in CTB, viral replication was significantly associated with enhanced cell fusion. In parallel, an increased number of SK was observed in infected placental areas in vivo compared to non-infected regions from the same placenta and to gestational age-matched controls. Altogether, these in vitro and in vivo results suggest that SARS-CoV-2 infection in early pregnancy may alter STB turnover, potentially contributing to placental dysfunction and adverse pregnancy outcomes.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"718"},"PeriodicalIF":9.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CTRP9 as a myokine mitigates sarcopenia via the LAMP-2A/NLRP3 pathway.","authors":"Linxi Li, Anju Zuo, Ruoyu Yin, Qiangqiang Liu, Chen Liu, Na Li, Dan Xu, Shaomeng Zhang, Jiarui Li, Shengyun Lei, Shiyan Ruan, Tingting Li, Yuan Guo","doi":"10.1038/s41419-025-08025-w","DOIUrl":"10.1038/s41419-025-08025-w","url":null,"abstract":"<p><p>Sarcopenia, a degenerative condition marked by progressive skeletal muscle atrophy and impaired regeneration, is closely associated with aging, chronic inflammation, and disrupted proteostasis. While macroautophagy has been extensively studied in this context, little of the role of chaperone-mediated autophagy (CMA) has been known. In this study, we identified C1q/TNF-related protein 9 (CTRP9) as a novel autocrine myokine secreted by skeletal muscle that exerts dual protective functions-pro-differentiative and anti-atrophic. By using a replicative senescence model in C2C12 myoblasts, we observed that CTRP9 expression declined with cellular aging, accompanied by reduced levels of lysosome-associated membrane protein type 2A (LAMP2A), increased nucleotide-binding domain, leucine-rich-containing family, and pyrin domain-containing-3 (NLRP3) accumulation, and elevated interleukin-1β (IL-1β) secretion. Similar molecular signatures were detected in skeletal muscle tissues of CTRP9 knockout (KO) mice, further validating its role in vivo. Treatment with the biologically active globular domain of CTRP9 (gCTRP9) restored LAMP2A expression, enhanced CMA activity, and promoted selective degradation of NLRP3, thereby alleviating inflammatory stress and cellular senescence. Functionally, gCTRP9 restored myogenic differentiation markers (e.g., MYOD1) while suppressing atrophy-related genes (e.g., Fbxo32) and improving fusion potential and myotube integrity. In primary human myoblasts isolated from elderly individuals, CTRP9 and LAMP2A were significantly downregulated, and NLRP3 expression was increased-changes that were partially reversed upon gCTRP9 treatment. These findings collectively demonstrate that the CTRP9-LAMP2A-NLRP3 axis plays a pivotal role in regulating both muscle regeneration and maintenance. By targeting CMA-mediated NLRP3 degradation, CTRP9 offers a promising therapeutic strategy for combating sarcopenia through coordinated modulation of differentiation pathways and muscle atrophy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"710"},"PeriodicalIF":9.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Helicobacter pylori-induced aberrant methylation of ID4 mediated by DNMT3B drives gastric cancer progression via DEC1-SHH signaling pathway.","authors":"Muhua Luan, Wenshuai Zhu, Zhaotian Feng, Fubo Jing, Yuanxin Xing, Xiaoli Ma, Yunshan Wang, Bin Ning, Yanfei Jia","doi":"10.1038/s41419-025-08042-9","DOIUrl":"10.1038/s41419-025-08042-9","url":null,"abstract":"<p><p>Helicobacter pylori (H. pylori) infection mediates activation of oncogenes and inhibition of tumor suppressor genes through aberrant DNA methylation, which is the predominant risk factor for gastric tumorigenesis. Here, by integrating transcriptome and epigenetic multi-omics analyses of gastric tissues and mouse models, we identified that inhibitor of differentiation 4 (ID4) was downregulated in H. pylori-infected gastric tissues and associated with prognosis of gastric cancer (GC). H. pylori infection remarkably increased the methylation level of the ID4 promoter region in the GC patients and mouse models. ID4 served as a tumor suppressor gene in GC and was required for H. pylori-mediated tumorigenic activities in vitro cellular and in vivo tumor-bearing mouse models. Moreover, H. pylori infection induced DNMT3B upregulation through recruiting KLF5 to its promoter and further promoted ID4 DNA methylation modification. Notably, ID4 formed heterodimers with the basic HLH transcription factors DEC1 to inhibit its transcriptional activity; therefore, downregulation of ID4 promoted SHH/GLI1 signaling through a DEC1 dependent transcriptional modulation. Collectively, our findings indicate H. pylori infection depends on DNMT3B to induce ID4 DNA methylation and ID4 promoter hypermethylation status is a potential biomarker to identify GC. Loss of ID4 could be a key component of H. pylori-mediated gastric tumorigenesis through dysregulation of DEC1/SHH/GLI1 axis, which provides potential therapeutic targets in GC.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"713"},"PeriodicalIF":9.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504463/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SNRPB promotes gastric cancer progression by regulating aberrant splicing of PUF60.","authors":"Dan Xiang, Jiaxin Yang, Miaofang Xiao, Cong Long, Yangxuan Lin, Chenchen Mao, Xin Liu, Dianfeng Mei, Wangkai Xie, Zheng Han, Chenbin Chen, Xiaoming Lin, Xian Shen, Xiangyang Xue, Tanzhou Chen","doi":"10.1038/s41419-025-08011-2","DOIUrl":"10.1038/s41419-025-08011-2","url":null,"abstract":"<p><p>Alternative splicing is a pivotal regulatory mechanism in cellular biology that critically influences the tumorigenesis, progression, and phenotypic diversity of cancer. This study aimed to assess the intricate details and regulatory mechanisms of alternative splicing in gastric cancer. We constructed a comprehensive map of aberrant alternative splicing events in gastric cancer through bioinformatic analysis of public databases and clinical samples. Our study identified many abnormal splicing events in gastric cancer tissues, with exon skipping being the most frequent event. SNRPB, a key spliceosome component and principal splicing factor, was associated with the aberrant splicing of numerous splicing factors and oncogenes, influencing the p53 signaling pathway in the development and progression of gastric cancer. SNRPB directly regulates the selective splicing of TP53 by modulating its downstream factor, PUF60, thus facilitating the initiation and progression of gastric cancer. Therefore, SNRPB overexpression is linked to poor prognosis in gastric cancer and is a potential biomarker and therapeutic target.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"709"},"PeriodicalIF":9.6,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}