Cell Discovery最新文献

{"title":"Bergeyella cardium variant induces a unique cytoplasmic vacuolization cell death floatptosis in macrophage.","authors":"Rudi Mao, Hongwei Pan, Luyu Yang, Zhenyu Fan, Yanfeng Li, Xinran Yu, Zhen Li, Ying Chen, Yang Yu, Wei Wang, Chengjiang Gao, Jun Peng, Tao Xu, Yi Zhang, Xiaopeng Qi","doi":"10.1038/s41421-025-00840-x","DOIUrl":"10.1038/s41421-025-00840-x","url":null,"abstract":"<p><p>Bacterial pathogens have evolved multiple mechanisms to modulate host cell death, evade host immunity, and establish persistent infection. Here, we show that an infective endocarditis causative pathogen, Bergeyella cardium, is frequently detected in oral specimens from clinical patients. A variant strain of Bergeyella cardium (BCV) induces unique cytoplasmic vacuolization cell death and minor apoptosis-like cell death in macrophages. The cytoplasmic vacuolization cell death triggered by BCV is characterized by Fused LysosOme-Associated Termination (floatptosis) and is inhibited by the sodium channel inhibitor amiloride. Moreover, outer membrane vesicles (OMVs) or transfection of barrel-like membrane proteins, lipocalin, β-barrel, and PorV, dramatically induce cytoplasmic vacuolization. Endosomal solute carrier family 9 member A9 (SLC9A9) plays important roles in the process of BCV-, OMVs-, and barrel-like proteins-triggered cytoplasmic vacuolization cell death via promoting vacuole fusion. SLC9A9 deficiency or amiloride administration increases host defense against BCV infection. These findings contribute to developing novel approaches to modulate cytoplasmic vacuolization cell death and treat infectious diseases.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"83"},"PeriodicalIF":12.5,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12537989/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145336458","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":"A pan-disease and population-level single-cell TCRαβ repertoire reference.","authors":"Ziwei Xue, Lize Wu, Bing Gao, Ruonan Tian, Yiru Chen, Yicheng Qi, Tianze Dong, Yadan Bai, Yu Zhao, Bing He, Lie Wang, Zuozhu Liu, Jianhua Yao, Linrong Lu, Wanlu Liu","doi":"10.1038/s41421-025-00836-7","DOIUrl":"10.1038/s41421-025-00836-7","url":null,"abstract":"<p><p>Recent advances in single-cell technology enable the simultaneous capture of T cell receptor (TCR) sequences and gene expression (GEX), providing an integrated view of T cell function. However, linking TCRαβ information and T cell phenotypes at the population level to elucidate their disease association remains an unaddressed gap. Here, by constructing a large-scale reference of paired single-cell RNA/TCR sequencing (scRNA/TCR-seq) comprising more than 2 million T cells from 70 studies, 1017 biological samples, 583 individuals, and 46 disease conditions, along with their single-cell transcriptome, full-length paired TCR, and human leukocyte antigen (HLA) genotypes, we revealed the intrinsic features of germline-encoded TCR-major histocompatibility complex (MHC) restriction in CD4⁺/CD8⁺ lineages. We also observed widely existing public TCRαβs across the population, associated with higher clonal expansion levels and shared HLA alleles. The most publicly shared TCRs are likely to target epitopes from common viruses, such as Epstein-Barr virus (EBV), cytomegalovirus (CMV), and influenza A virus (IAV). Furthermore, we introduced TCR-DeepInsight, a computational framework to identify HLA-shared and disease-associated TCRαβ clusters that exhibit similar TCR sequence and GEX profiles, extensible for researchers to incorporate their data with our reference and characterize potentially functional TCRs. In summary, our work presents a panoramic scTCRαβ reference and computational methods for TCR study.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"82"},"PeriodicalIF":12.5,"publicationDate":"2025-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12521495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291259","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":"Ferroptosis-induced SUMO2 lactylation counteracts ferroptosis by enhancing ACSL4 degradation in lung adenocarcinoma.","authors":"Guangyao Shan, Yunyi Bian, Qihai Sui, Jiaqi Liang, Shencheng Ren, Binyang Pan, Haochun Shi, Zhaolin Zheng, Dejun Zeng, Junkan Zhu, Zhencong Chen, Guoshu Bi, Hong Fan, Cheng Zhan","doi":"10.1038/s41421-025-00829-6","DOIUrl":"10.1038/s41421-025-00829-6","url":null,"abstract":"<p><p>Lactylation, a lactate-mediated post-translational modification, has garnered significant attention for its pivotal role in epigenetic modulation. However, the intricate interplay between lactylation and ferroptosis in lung adenocarcinoma (LUAD) remains to be fully elucidated. Utilizing metabolomic profiling and comprehensive metabolic library screening, our study uncovers that ferroptosis markedly enhances lactic acid accumulation and subsequent protein lactylation, which in turn confers resistance to ferroptosis in LUAD cells. Functional assays, comprising cell viability tests, lipid peroxidation detection, as well as malondialdehyde and glutathione measurements, collectively reveal that SUMO2-K11 lactylation (SUMO2-K11la), the most prominently elevated lactylation in response to ferroptosis induction, serves as a pivotal factor in determining ferroptosis resistance. Sumoylation proteomics and co-immunoprecipitation assays reveal that SUMO2-K11la impairs the interaction between SUMO2 and ACSL4. Consequently, this disruption facilitates the degradation of ACSL4, thereby disrupting lipid metabolism and effectively mitigating ferroptosis. Furthermore, AARS1 is identified as the lactyltransferase and HDAC1 as the delactylase for SUMO2-K11la. Based on these findings, we develop a cell-penetrating peptide that competitively and specifically inhibits SUMO2-K11la. This peptide significantly potentiates ferroptosis and sensitizes LUAD to cisplatin in xenograft models, while enhancing chemoimmunotherapy responses in spontaneous lung cancer models. Overall, our findings imply that SUMO2-K11la is a pivotal regulator of ferroptosis resistance in LUAD, and suggest a promising strategy to potentiate ferroptosis-based cancer therapies via targeting SUMO2-K11la by the cell-penetrating peptide.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"81"},"PeriodicalIF":12.5,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12504568/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145243947","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":"Suppressing protein damage response to overcome multidrug resistance in cancer therapy.","authors":"Fangyuan Shao, Zongjie Li, Hao Xiao, Yujun Chen, Yuheng Zhang, Ling Li, Yuzhong Peng, Xinyi Li, Yuxing Hou, Bo Li, Xiangpeng Chu, Maoxin Ran, Dongyang Tang, Xi Han, Jiaxin Yao, Cuiting Zhang, Lijian Wang, Haifeng Li, Nan Shao, Kai Miao, Xiaoling Xu, Yanxia Shi, Changhua Zhang, Jun Yan, Ying Lin, Chu-Xia Deng","doi":"10.1038/s41421-025-00826-9","DOIUrl":"10.1038/s41421-025-00826-9","url":null,"abstract":"<p><p>Multidrug resistance is a significant barrier in cancer therapy largely due to poorly understood regulatory mechanisms. Here we reveal that certain anticancer drugs can bind to newly synthesized proteins prior to reaching their canonical targets, resulting in various forms of protein damage. This binding disrupts protein functions, particularly those of mitochondrial proteins, resulting in substantial cytotoxicity. The protein damage is further exacerbated by mitochondrial reactive oxygen species generated as a consequence of the initial damage, creating a positive feedback loop. In response, cancer cells rapidly initiate a chain of events, which we term the Protein Damage Response (PDR). This includes damage recognition primarily mediated by protein ubiquitination and subsequent damage clearance via the proteasome system. Notably, patients with advanced, drug-resistant metastatic breast or colon cancers exhibit elevated proteasome activity. In an effort to predict drug resistance, we developed a sensitive kit for detecting proteasome levels, enabling the identification and subtyping of patients with high proteasome activity to support tailored therapeutic strategies. Using a three-dimensional tumor slice culture-based drug sensitivity assay and an investigator-initiated clinical trial, we demonstrate that three clinically approved proteasome inhibitors effectively overcome multidrug resistance in colon and breast cancer patients with elevated proteasome activity.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"80"},"PeriodicalIF":12.5,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12484725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198424","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":"Chemosensation of the pheromone spermine by the olfactory TAAR-like receptor TAAR348.","authors":"Kexin Jiang, Liting Zeng, Weifeng Zhang, Xuefei He, You Zheng, Ling Wang, Zhongyuan Zhang, Jun Pu, Cheng Deng, Fan Yang, Suwen Zhao, Fei Xu","doi":"10.1038/s41421-025-00839-4","DOIUrl":"10.1038/s41421-025-00839-4","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"79"},"PeriodicalIF":12.5,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12476453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145181824","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":"MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity.","authors":"Pallavi Asthana, Liguo Li, Lin Lu, Jiayan Wu, Shuo Zhang, Ningning Li, Sheung Kin Ken Wong, Susma Gurung, Yijing Zhang, Yuwan Lin, Yufeng Peng, Zongtang Xu, Kui Ming Chan, Lixiang Zhai, Aiping Lyu, Zhao-Xiang Bian, Xin Ge, Ashok Iyaswamy, Min Li, Ya Su, Zhongjun Zhou, Pingyi Xu, Hoi Leong Xavier Wong","doi":"10.1038/s41421-025-00825-w","DOIUrl":"10.1038/s41421-025-00825-w","url":null,"abstract":"<p><p>Obesity has been linked to an increased risk of cognitive impairment and dementia in later life. Although aging and obesity are both associated with cognitive decline, it remains unclear how they interact to affect cognitive function across the lifespan and how brain function might mediate their relationship with cognition. Our previous findings and other studies have shown that membrane type 1-matrix metalloproteinase (MT1-MMP/MMP14), which increases with age, regulates energy homeostasis. Inhibiting MT1-MMP improves insulin sensitivity, reduces body fat, and lowers serum cholesterol. Here, we demonstrate that MT1-MMP links neuroinflammation to cognitive decline in aging and obesity. Inflammatory responses in the brain increase MT1-MMP activation in the hippocampus of both mice and humans. Activation of hippocampal MT1-MMP alone can trigger cognitive decline and synaptic impairment independently of neuroinflammation. Conversely, ablation of MT1-MMP in the hippocampus reverses cognitive decline and improves synaptic plasticity in aging and obesity. Pharmacological inhibition of MT1-MMP, through an orally administered brain-penetrant inhibitor or targeted delivery of a neutralizing antibody to the hippocampus, improves memory and learning in aged and obese mice without toxicity. Mechanistically, MT1-MMP proteolytically inactivates G-protein-coupled receptor 158 (GPR158), a hippocampal receptor for osteocalcin (OCN) that is important for the maintenance of cognitive integrity, thus suppressing the ability of the OCN-GPR158 axis to promote cognition in aging and obesity. These findings suggest a new mechanism underlying hippocampal dysfunction and reveal the potential for treating multiple age-related diseases, including neurodegenerative disorders, obesity, diabetes, and atherosclerosis, with a single MT1-MMP-blocking agent.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"76"},"PeriodicalIF":12.5,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12454644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145124275","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":"Molecular mechanisms of PI3Kα activation by small-molecule activator 1938 and cancer-specific mutation H1047R.","authors":"Xiao Liu, Qingtong Zhou, Yanyan Chen, Wei Han, Jie Li, Yiting Mai, Ming-Wei Wang","doi":"10.1038/s41421-025-00833-w","DOIUrl":"10.1038/s41421-025-00833-w","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"77"},"PeriodicalIF":12.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12446426/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145085101","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":"Author Correction: The Asprosin-OLFR734 hormonal signaling axis modulates male fertility.","authors":"Fangchao Wei, Aijun Long, Yiguo Wang","doi":"10.1038/s41421-025-00834-9","DOIUrl":"10.1038/s41421-025-00834-9","url":null,"abstract":"","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"78"},"PeriodicalIF":12.5,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12449444/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091190","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":"STK4 inhibits the E3 activity of HOIP by phosphorylating its allosteric ubiquitin-binding site.","authors":"Yaru Wang, Xindi Zhou, Zhiqiao Lin, Yichao Huang, Yuchao Zhang, Haobo Liu, Yuqian Zhou, Jianping Liu, Lifeng Pan","doi":"10.1038/s41421-025-00824-x","DOIUrl":"10.1038/s41421-025-00824-x","url":null,"abstract":"<p><p>HOIP, an RBR-type E3 ligase and the catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC), plays crucial roles in various cellular processes, including the NF-κB signaling pathway. The E3 activity of HOIP can be inhibited by the kinase STK4-mediated phosphorylation, although the mechanism is poorly understood. In this study, using biochemical, mass spectrometry and structural approaches, we systemically characterize the association of STK4 with HOIP, and unveil that STK4 can directly bind to the RING2-LDD module of HOIP through its kinase domain. The determined crystal structure of STK4 in complex with HOIP RING2-LDD not only elucidates the detailed binding mechanism of STK4 with HOIP, but also uncovers, for the first time, a unique binding mode of STK4 with its substrate. Moreover, we reveal that STK4 can directly phosphorylate the T786 residue of HOIP that is located in the allosteric ubiquitin-binding site of HOIP. Importantly, the phosphorylation of HOIP T786 mediated by STK4 can block the binding of ubiquitin to the allosteric site of HOIP, thereby attenuating the E3 activity of HOIP. In all, our findings provide mechanistic insights into the interaction between STK4 and HOIP as well as the negative regulation of HOIP's E3 activity by STK4-mediated phosphorylation, which are valuable for further understanding the regulatory modes of RBR-type E3 ligases.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"75"},"PeriodicalIF":12.5,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12441119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145074400","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":"Intrauterine hyperglycemia impairs mouse primordial germ cell development and fertility by sex-specific epigenetic reprogramming interference.","authors":"Jiangshan Cong, Qing Li, Yangyang Li, Minghao Li, Yan Shi, Peiran Hu, Xidi Yin, Qianyun Zhang, Jianzhong Sheng, Jinsong Li, Guolian Ding, Yu Zhang, Hefeng Huang","doi":"10.1038/s41421-025-00821-0","DOIUrl":"10.1038/s41421-025-00821-0","url":null,"abstract":"<p><p>Adverse intrauterine environments, such as hyperglycemia, impair sexual reproduction and species continuity, yet the underlying mechanisms remain poorly understood. In this study, we demonstrated that intrauterine hyperglycemia significantly disrupted primordial germ cell (PGC) development, especially in female offspring, thus reducing fertility. Using Oct4-EGFP transgenic mice with intrauterine hyperglycemia exposure, we revealed that hyperglycemia compromised sexually specific chromatin accessibility and DNA methylation reprogramming during PGC development. Particularly, in female PGCs, hyperglycemia leads to the aberrant retention of chromatin accessibility at pluripotency gene promoters such as Nanog and Tfap2c, inhibiting proper gene silencing and blocking the initiation of meiosis, which ultimately hinders oocyte maturation. Conversely, male PGCs exhibit less severe changes in chromatin accessibility and gene transcription. Intriguingly, the global DNA methylation reconstruction is impaired in male PGCs, particularly in key imprinted gene regions, suggesting potential developmental ramifications for later stages and even subsequent generations. Particularly, our findings indicate that intrauterine hyperglycemia adversely affects sex differentiation in PGCs by disrupting the expression of critical sex-determining transcription factors. Collectively, these findings highlight how intrauterine hyperglycemia interferes with sex-specific epigenetic reprogramming during PGC development, leading to abnormal germ cell development, reduced fertility, and adverse intergenerational effects.</p>","PeriodicalId":9674,"journal":{"name":"Cell Discovery","volume":"11 1","pages":"74"},"PeriodicalIF":12.5,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12417548/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145022820","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}