Cell Death & Disease最新文献

{"title":"High glucose levels promote glycolysis and cholesterol synthesis via ERRα and suppress the autophagy-lysosomal pathway in endometrial cancer.","authors":"Xiaodan Mao, Lixiang Huang, Xianhua Liu, Xite Lin, Qibin Wu, Xinrui Wang, Yuan Ren, Jincheng Ma, Maotong Zhang, Yao Lin, Damian J Ralser, Alexander Mustea, Gang Chen, Pengming Sun","doi":"10.1038/s41419-025-07499-y","DOIUrl":"10.1038/s41419-025-07499-y","url":null,"abstract":"<p><p>Endometrial cancer (EC) patients with Diabetes Mellitus (DM) always have a poor prognosis. Estrogen-related receptor α (ERRα) is known as the metabolic-related prognostic factor for EC. However, the mechanism linking glycolipid metabolism dysfunction mediated by ERRα to poor prognosis of EC with DM is still unclear. In vitro, high-glucose (HG) levels showed enhancement of ERRα expression, cell proliferation, and inhibition of the autophagic lysosomes and apoptosis by flow cytometry analysis, transmission electron microscopy, and CCK-8 assays. Mechanistically, lose-and-gain function assay, DNA sequencing, and CO-IP revealed HG increased ERRα expression to promote the transcription of HK2 and HMGCS1, which were the key rate-limiting enzyme of glycolysis-cholesterol synthesis and their metabolites suppressed the autophagy-lysosomal pathway in an ERRα-dependent manner. Furthermore, CO-IP and molecular dynamics simulation uncovered the protein residues (ARG 769_HK2 vs. ARG 313_HMGCS1) of HK2 and HMGCS1 could bind to p62 to form stable protein complexes involved in the autophagy-lysosomal pathway. In EC tissue from patients with comorbid DM, ERRα was significantly higher expressed compared to EC tissue from patients without evidence for DM (p < 0.05). The 3D EC organoid model with HG stimulation showed that the cell viability of XCT790 + carboplatin treatment was similar to that of metformin+carboplatin treatment, while the obviously bigger volume of organoids was more visible in the metformin+carboplatin group, indicating the therapy of XCT790 + carboplatin had the better inhibition of EC organoids with the same carboplatin dose. Besides insights into the interaction of HG and the autophagy-lysosomal pathway via ERRα, our present study points out the potential benefit of targeting ERRα in patients with EC with dysregulation of glucose and cholesterol metabolism.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"182"},"PeriodicalIF":8.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647131","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":"Correction: Cardiac-specific CGI-58 deficiency activates the ER stress pathway to promote heart failure in mice.","authors":"Xin Xie, Yi-Fan Tie, Song Lai, Yun-Long Zhang, Hui-Hua Li, Ying Liu","doi":"10.1038/s41419-025-07370-0","DOIUrl":"10.1038/s41419-025-07370-0","url":null,"abstract":"","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"180"},"PeriodicalIF":8.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647099","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":"Therapeutic targeting de novo purine biosynthesis driven by β-catenin-dependent PPAT upregulation in hepatoblastoma.","authors":"Ming Ding, Chunshuang Ma, Yanyan Lin, Houshun Fang, Yan Xu, Shuxuan Wang, Yao Chen, Jiquan Zhou, Hongxiang Gao, Yuhua Shan, Liyuan Yang, Huiying Sun, Yabin Tang, Xiaoyu Wu, Liang Zhu, Liang Zheng, Yehuda G Assaraf, Bin-Bing S Zhou, Song Gu, Hui Li","doi":"10.1038/s41419-025-07502-6","DOIUrl":"10.1038/s41419-025-07502-6","url":null,"abstract":"<p><p>De novo purine biosynthesis (DNPS) was previously shown to be aberrantly activated in many cancers. However, the activity of DNPS pathway and its underlying regulatory mechanism in hepatoblastoma (HB) remain poorly understood. Herein, we discovered that the expression of PPAT, the rate-limiting enzyme in DNPS, was markedly upregulated in HB, leading to an augmented purine flux via DNPS, thereby promoting both HB cell proliferation and migration. Furthermore, we found that activated mutant β-catenin, a dominant driver of HB, transcriptionally activated PPAT expression, hence stimulating DNPS and constituting a druggable metabolic vulnerability in HB. Consistently, pharmacological targeting using a DNPS inhibitor lometrexol or genetic repressing the enhanced DNPS markedly blocked HB progression in vitro and in vivo. Our findings suggest that HB patients harboring activated β-catenin mutations and consequent DNPS upregulation, may be treated efficaciously with DNPS enzyme inhibitors like lometrexol. These novel findings bear major therapeutic implications for targeted precision medicine of HB.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"179"},"PeriodicalIF":8.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11914223/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143647288","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":"Core N-DRC components play a crucial role in embryonic development and postnatal organ development.","authors":"Chuan Ren, Shuya Sun, Jiajie Zhu, Shushu Zhou, Xin Zhang, Shuhui Bian, Ying Wang, Jintao Zhang, Mingxi Liu","doi":"10.1038/s41419-025-07506-2","DOIUrl":"10.1038/s41419-025-07506-2","url":null,"abstract":"<p><p>Motile cilia and flagella are evolutionarily conserved organelles, and their defects cause primary ciliary dyskinesia (PCD), a disorder characterized by systemic organ dysfunction. The nexin-dynein regulatory complex (N-DRC) is a crucial structural component of motile cilia and flagella, present across various species from Chlamydomonas to humans. Defects in N-DRC components lead to multiple PCD symptoms, including sinusitis and male infertility. However, the phenotypic expression of N-DRC defects varies significantly among individuals, and there has been a lack of systematic study of core N-DRC components in mammals. Utilizing Drc1-4 and Drc7 knockout mice, this study systematically reveals the roles and assembly process of core N-DRC components in ependymal cilia, respiratory cilia, and sperm flagella. The findings show that core N-DRC components are crucial for the survival of mice on a purebred genetic background. In mixed genetic background mice, N-DRC defects impair the motility of motile cilia and the stability of flagellar axonemes. Additionally, a novel role of the N-DRC specific component (A-kinase anchoring protein 3) AKAP3 in regulating sperm phosphorylation was discovered. Collectively, our results provide a comprehensive understanding of the core N-DRC components in mammalian cilia and flagella.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"176"},"PeriodicalIF":8.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910659/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633731","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":"Genetic deletion of G protein-coupled receptor 56 aggravates traumatic brain injury through the microglial CCL3/4/5 upregulation targeted to CCR5.","authors":"Zhuang Sha, Shiying Dong, Meng Nie, Tao Liu, Chenrui Wu, Chuanxiang Lv, Mingqi Liu, Weiwei Jiang, Jiangyuan Yuan, Yu Qian, Xianhua Piao, Rongcai Jiang, Chuang Gao","doi":"10.1038/s41419-025-07501-7","DOIUrl":"10.1038/s41419-025-07501-7","url":null,"abstract":"<p><p>Traumatic brain injury (TBI) is a significant global health concern that often results in death or disability, and effective pharmacological treatments are lacking. G protein-coupled receptor 56 (GPR56), a potential drug target, is crucial for neuronal and glial cell function and therefore plays important roles in various neurological diseases. Here, we investigated the potential role and mechanism of GPR56 in TBI-related damage to gain new insights into the pharmacological treatment of TBI. Our study revealed that TBI caused a significant decrease in GPR56 expression and that the deletion of Gpr56 exacerbated neurological function deficits and blood‒brain barrier (BBB) damage following TBI. Additionally, Gpr56 deletion led to increased microgliosis, increased infiltration of peripheral T cells and macrophages, and increased release of cerebral inflammatory cytokines and chemokines after TBI. Furthermore, Gpr56 deletion induced neuronal apoptosis, impaired autophagy, and exacerbated neurological function deficits through microglial-to-neuronal CCR5 signaling after TBI. Overall, these results indicate that Gpr56 knockout exacerbates neurological deficits, neuroinflammation and neuronal apoptosis following TBI through microglial CCL3/4/5 upregulation targeted to CCR5, which indicates that GRP56 may be a potential new pharmacological target for TBI.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"175"},"PeriodicalIF":8.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910551/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633736","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":"CKMT1 deficiency contributes to mitochondrial dysfunction and promotes intestinal epithelial cell apoptosis via reverse electron transfer-derived ROS in colitis.","authors":"Zhijie Wang, Haicong Wu, Xin Chang, Yihang Song, Yan Chen, Ziwei Yan, Lun Gu, Ruxi Pang, Tian Xia, Zixuan He, Zhaoshen Li, Shuling Wang, Yu Bai","doi":"10.1038/s41419-025-07504-4","DOIUrl":"10.1038/s41419-025-07504-4","url":null,"abstract":"<p><p>Mitochondrial dysfunction contributes to the pathogenesis of ulcerative colitis (UC). As a mitochondrial isozyme of creatine kinases, which control energy metabolism, CKMT1 is thought to be a critical molecule in biological processes. However, the specific role of CKMT1 in intestinal inflammation remains largely unknown. Here, we observed markedly decreased CKMT1 expression in the colon tissues of UC patients and dextran sodium sulfate (DSS)-induced colitis mice. We generated intestinal epithelial-specific CKMT1 knockout mice and demonstrated the key role of CKMT1 in mitochondrial homeostasis, intestinal epithelial barrier function, oxidative stress, and apoptosis. In the in vitro experiments, CKMT1 expression limited the activation of the intrinsic and extrinsic apoptotic pathways in IECs. Mechanistically, the loss of CKMT1 expression in IECs increased TNF-α-induced mitochondrial reactive oxygen species (ROS) generation via reverse electron transfer (RET). RET-ROS promoted mitochondrial permeability transition pore (mPTP) opening, ultimately resulting in cell apoptosis during intestinal inflammation. In conclusion, our data demonstrated that CKMT1 is important in maintaining intestinal homeostasis and mitochondrial function. This study provides a promising basis for future research and a potential therapeutic target for inflammatory bowel disease (IBD).</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"177"},"PeriodicalIF":8.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11910573/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633727","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":"TIMM23 overexpression drives NSCLC cell growth and survival by enhancing mitochondrial function.","authors":"Jianhua Zha, Jiaxin Li, Hui Yin, Mingjing Shen, Yingchen Xia","doi":"10.1038/s41419-025-07505-3","DOIUrl":"10.1038/s41419-025-07505-3","url":null,"abstract":"<p><p>Mitochondrial hyperfunction is implicated in promoting non-small cell lung cancer (NSCLC) cell growth. TIMM23 (translocase of inner mitochondrial membrane 23) is a core component of the mitochondrial import machinery, facilitating the translocation of proteins across the inner mitochondrial membrane into the matrix. Its expression and potential functions in NSCLC were tested. Comprehensive bioinformatic analysis revealed a strong correlation between TIMM23 overexpression and adverse clinical outcomes in NSCLC patients. Single-cell RNA sequencing data further corroborated these findings, demonstrating elevated TIMM23 expression within the cancer cells of NSCLC mass. Subsequent experimental validation confirmed significantly increased TIMM23 mRNA and protein levels in locally-treated NSCLC tissues compared to matched normal lung tissues. Moreover, TIMM23 expression was consistently elevated across multiple primary/established NSCLC cells. Silencing or ablation of TIMM23 via shRNA or CRISPR/Cas9 in NSCLC cells resulted in impaired mitochondrial function, characterized by reduced complex I activity, ATP depletion, mitochondrial membrane potential dissipation, oxidative stress, and lipid peroxidation. These mitochondrial perturbations coincided with attenuated cell viability, proliferation, and migratory capacity, and concomitant induction of apoptosis. Conversely, ectopic overexpression of TIMM23 significantly enhanced mitochondrial complex I activity and ATP production, promoting NSCLC cell proliferation and motility. In vivo, intratumoral delivery of a TIMM23 shRNA-expressing adeno-associated virus significantly suppressed the growth of subcutaneous NSCLC xenografts in nude mice. Subsequent analysis of tumor tissues revealed depleted TIMM23 expression, ATP reduction, oxidative damage, proliferative arrest, and apoptotic induction. Collectively, these findings establish TIMM23 as a critical pro-tumorigenic factor in NSCLC, highlighting its potential as a prognostic biomarker and therapeutic target.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"174"},"PeriodicalIF":8.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11906786/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623777","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":"Both direct and indirect suppression of MCL1 synergizes with BCLXL inhibition in preclinical models of gastric cancer.","authors":"Li-Ping Zhang, Yu-Min Wei, Ming-Jie Luo, Shu-Yue Ren, Xiang-Wen Zhan, Chao Wang, Ze-Feng Li, Rui-Min Zhu, Shuo Yan, Yu Cheng, Jia-Li Xu, Xing-Jiu Yang, Ke-Lei Du, Jin-Qing Wang, Guan-Nan Zhang, De-Xiao Du, Ran Gao, Dong-Bing Zhao, Jia-Nan Gong","doi":"10.1038/s41419-025-07481-8","DOIUrl":"10.1038/s41419-025-07481-8","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Despite the progress of treatment in gastric cancer (GC), the overall outcomes remain poor in patients with advanced diseases, underscoring the urgency to develop more effective treatment strategies. BH3-mimetic drugs, which inhibit the pro-survival BCL2 family proteins, have demonstrated great therapeutic potential in cancer therapy. Although previous studies have implicated a role of targeting the cell survival pathway in GC, the contribution of different pro-survival BCL2 family proteins in promoting survival and mediating resistance to current standard therapies in GC remains unclear. A systematic study to elucidate the hierarchy of these proteins using clinically more relevant GC models is essential to identify the most effective therapeutic target(s) and rational combination strategies for improving GC therapy. Here, we provide evidence from both in vitro and in vivo studies using a broad panel of GC cell lines, tumoroids, and xenograft models to demonstrate that BCLXL and MCL1, but not other pro-survival BCL2 family proteins, are crucial for GC cells survival. While small molecular inhibitors of BCLXL or MCL1 exhibited some single-agent activity, their combination sufficed to cause maximum killing. However, due to the unsolved cardiotoxicity associated with direct MCL1 inhibitors, finding combinations of agents that indirectly target MCL1 and enable the reduction of doses of BCLXL inhibitors while maintaining their anti-neoplastic effects is potentially a feasible approach for the further development of these compounds. Importantly, inhibiting BCLXL synergized significantly with anti-mitotic and HER2-targeting drugs, leading to enhanced anti-tumour activity with tolerable toxicity in preclinical GC models. Mechanistically, anti-mitotic chemotherapies induced MCL1 degradation via the ubiquitin-proteasome pathway mainly through FBXW7, whereas HER2-targeting drugs suppressed MCL1 transcription via the STAT3/SRF axis. Moreover, co-targeting STAT3 and BCLXL also exhibited synergistic killing, extending beyond HER2-amplified GC. Collectively, our results provide mechanistic rationale and pre-clinical evidence for co-targeting BCLXL and MCL1 (both directly and indirectly) in GC. (i) Gastric cancer cells rely on BCLXL and, to a lesser degree, on MCL1 for survival. The dual inhibition of BCLXL and MCL1 with small molecular inhibitors acts synergistically to kill GC cells, regardless of their TCGA molecular subtypes or the presence of poor prognostic markers. While the effect of S63845 is mediated by both BAX and BAK in most cases, BAX, rather than BAK, acts as the primary mediator of BCLXLi in GC cells. (ii) Inhibiting BCLXL significantly synergizes with anti-mitotic and HER2-targeting drugs, leading to enhanced anti-tumour activity with tolerable toxicity in preclinical GC models. Mechanistically, anti-mitotic chemotherapies induce MCL1 degradation via the ubiquitin-proteasome pathway mainly through FBXW7, whereas HER2-targeting drugs suppre","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"170"},"PeriodicalIF":8.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11904182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613678","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":"Point mutations of the mitochondrial chaperone TRAP1 affect its functions and pro-neoplastic activity.","authors":"Claudio Laquatra, Alessia Magro, Federica Guarra, Matteo Lambrughi, Lavinia Ferrone, Giulio Fracasso, Melissa Bacchin, Martina La Spina, Elisabetta Moroni, Elena Papaleo, Giorgio Colombo, Andrea Rasola","doi":"10.1038/s41419-025-07467-6","DOIUrl":"10.1038/s41419-025-07467-6","url":null,"abstract":"<p><p>The mitochondrial chaperone TRAP1 is a key regulator of cellular homeostasis and its activity has important implications in neurodegeneration, ischemia and cancer. Recent evidence has indicated that TRAP1 mutations are involved in several disorders, even though the structural basis for the impact of point mutations on TRAP1 functions has never been studied. By exploiting a modular structure-based framework and molecular dynamics simulations, we investigated the effect of five TRAP1 mutations on its structure and stability. Each mutation differentially impacts long-range interactions, intra and inter-protomer dynamics and ATPase activity. Changes in these parameters influence TRAP1 functions, as revealed by their effects on the activity of the TRAP1 interactor succinate dehydrogenase (SDH). In keeping with this, TRAP1 point mutations affect the growth and migration of aggressive sarcoma cells, and alter sensitivity to a selective TRAP1 inhibitor. Our work provides new insights on the structure-activity relationship of TRAP1, identifying crucial amino acid residues that regulate TRAP1 proteostatic functions and pro-neoplastic activity.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"172"},"PeriodicalIF":8.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903959/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613681","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 effect of TIM1⁺ Breg cells in liver ischemia-reperfusion injury.","authors":"Yu Zhang, Cheng Zhang, Beng Yang, Chuanhui Peng, Jie Zhou, Shenli Ren, Zhenhua Hu","doi":"10.1038/s41419-025-07446-x","DOIUrl":"10.1038/s41419-025-07446-x","url":null,"abstract":"<p><p>Liver transplantation is the only effective method for end-stage liver disease; however, liver ischemia reperfusion injury (IRI) seriously affects donor liver function after liver transplantation. IRI is a pathophysiological process in which organ damage is aggravated after the blood flow and oxygen supply of ischemic organ tissues are restored. It combines the two stages of hypoxic cell stress triggered by ischemia and inflammation-mediated reperfusion injury. Herein, we studied the protective effect and mechanism of the anti-T cell Ig and mucin domain (TIM1) monoclonal antibody, RMT1-10, on hepatic cell injury induced by IRI. First, a liver IRI model was established in vivo. HE, TEM, and Tunel were used to detect liver tissue injury, changes in the liver ultrastructure and liver cell apoptosis, respectively. ELISA were performed to determine the levels of ALT, AST, MDA, GSH, and related inflammatory factors. We found that RMT1-10 could significantly reduce liver injury. Flow cytometry results showed that the number of TIM1⁺ regulatory B cells (Bregs) in the IRI liver increased briefly, while pretreatment with RMT1-10 could increase the number of TIM1⁺ Bregs and interleukin-10 (IL-10) secretion in liver IRI model mice, thus playing a protective role in liver reperfusion. When Anti-CD20 was used to remove B cells, RMT1-10 had a reduced effect on liver IRI. Previous data showed that the number of T helper 1 cells (Th1:CD4⁺; CD8⁺) increased significantly after IRI. RMT1-10 inhibited Th1 cells; however, it significantly activated regulatory T cells. Sequencing analysis showed that RMT1-10 could significantly downregulate the expression of nuclear factor-kappa B (NF-κB) pathway-related genes induced by IRI. These results suggested that RMT1-10 could promote the maturation of B cells through an atypical NF-κB pathway, thereby increasing the number of TIM1⁺ Bregs and associated IL-10 secretion to regulate the inflammatory response, thereby protecting against liver IRI.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"171"},"PeriodicalIF":8.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11903774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613683","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}