Cell Death and Differentiation最新文献

{"title":"GSDME-mediated pyroptosis in microglia exacerbates demyelination and neuroinflammation in multiple sclerosis: insights from humans and cuprizone-induced demyelination model mice","authors":"Danjie Wang, Tongtong Zhang, Qi Shao, Xinyi Wu, Xiaoqiang Zhao, Hongyu Zhang, Yumeng Wang, Jingxian Sun, Xuechun Chang, Keying Zhu, Shuai Wu, Li Cao, Wankun Chen, Jun Wang","doi":"10.1038/s41418-025-01537-0","DOIUrl":"https://doi.org/10.1038/s41418-025-01537-0","url":null,"abstract":"<p>Demyelination, a hallmark of multiple sclerosis (MS), disrupts neural conduction due to myelin sheath degradation. Microglia-mediated inflammation plays a pivotal role in this process, with emerging evidence implicating gasdermin E (GSDME) in neuroinflammation and neurodegeneration. However, the specific role of GSDME in MS remains unclear. Here, we investigated the involvement of GSDME in MS using brain tissues from MS patients and cuprizone (CPZ)-induced demyelination model mice. We observed elevated GSDME expression in the central nervous system (CNS) lesions of MS patients, with pronounced GSDME cleavage in microglia at injury sites. Genetic knockout of <i>Gsdme</i> alleviated CPZ-induced motor deficits, demyelination, and neuroinflammation. Furthermore, caspase-3 inhibition significantly suppressed GSDME activation, resulting in reduced demyelination, motor coordination impairment, and neuroinflammation. In an experimental autoimmune encephalomyelitis (EAE) model, caspase-3/GSDME-mediated microglial pyroptosis critically mediated the progression of neuroinflammation and white matter demyelination. Transcriptome sequencing revealed that GSDME regulated the expression of genes related to disease-associated microglia (DAMs) and impaired microglial autophagy, a process critical for myelin debris clearance. <i>Gsdme</i> knockout downregulated the expression of genes associated with DAMs and CPZ-induced microglia-driven demyelination while increasing the expression of remyelination-related genes (<i>Cybb</i> and <i>Cd74</i>). In vitro, GSDME suppression promoted microglial autophagy and myelin debris clearance. Collectively, our findings highlight GSDME-mediated pyroptosis as a key driver of demyelination and neuroinflammation in MS, suggesting novel therapeutic targets for neuroinflammatory disorders.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"36 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144479013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cullin-associated and neddylation-dissociated protein 1 (CAND1) promotes cardiomyocyte proliferation and heart regeneration by enhancing the ubiquitinated degradation of Mps one binder kinase activator 1b (Mob1b)","authors":"Xingda Li, Lingmin Zhang, Tao Tian, Yao Pei, Kaile Wang, Shuang Wang, Xuan Ning, Pinhan Zhao, Yueying Qu, Haiyu Gao, Chenhong Li, Xuening Liu, Jiming Yang, Yingzi Zhang, Hongbin Gao, Lina Xuan, Yang Zhang, Yanjie Lu, Benzhi Cai, Baofeng Yang, Zhenwei Pan","doi":"10.1038/s41418-025-01540-5","DOIUrl":"https://doi.org/10.1038/s41418-025-01540-5","url":null,"abstract":"<p>Activation of the intrinsic regenerative potential of adult mammalian hearts by promoting cardiomyocyte proliferation holds great potential in heart repair. CAND1 (Cullin-associated and neddylation-dissociated protein 1) functions as a critical regulator of cellular protein homeostasis by fine-tuning the ubiquitinated degradation of specific abnormally expressed protein substrates. Here, we identified that cardiac-specific transgenic overexpression of CAND1 reduced the infarct size, restored cardiac function, and promoted cardiomyocyte proliferation after myocardial infarction in juvenile (7-day-old) and adult (8-week-old) mice. Conversely, CAND1 deficiency blunted the regenerative capacity of neonatal hearts after apex resection. MS and functional verification demonstrated that CAND1 enhanced the assembly of Cullin1, FBXW11(F-box/WD repeat-containing protein 11), and Mob1b (Mps one binder kinase activator 1b) complexes, and thus promotes the degradation of Mob1b. The ubiquitination of Mob1b occurred at K108 and was linked by K48 of ubiquitin. Mob1b deletion partially rescued the loss of regenerative capacity in neonatal hearts induced by CAND1 deficiency and improved cardiac function in adult mice post-MI. Moreover, CAND1 promoted the proliferation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Our data demonstrate that CAND1 promotes cardiomyocyte proliferation via FBXW11-mediated K48-linked ubiquitination degradation of Mob1b, and improves heart regeneration after cardiac injury. The findings provide a novel strategy to promote cardiac regeneration and repair.</p><figure><p>Schematic diagram of the role of CAND1 in regulating ubiquitination and degradation of Mob1b and cardiomyocyte proliferation and heart regeneration. Under CAND1-High condition, CAND1 promotes the incorporation of Cullin1, FBXW11, and Mob1b complexes, and accelerates SCF^FBXW11-mediated K48-linked ubiquitination of Mob1b at the K108 site, which leads to the degradation of Mob1b and thus suppresses the Hippo signaling pathway and facilitates cardiomyocyte proliferation and heart regeneration post-MI.</p></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"45 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144371137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synergistic targeting of cancer cells through simultaneous inhibition of key metabolic enzymes","authors":"Jan Dreute, Julia Stengel, Jonas Becher, David van den Borre, Maximilian Pfisterer, Marek Bartkuhn, Vanessa M. Beutgen, Benardina Ndreshkjana, Ulrich Gärtner, Johannes Graumann, Michael Huck, Stephan Klatt, Chloe Leff, Henner F. Farin, Andrea Nist, Roland Schmitz, Thorsten Stiewe, Julia Teply-Szymanski, Jochen Wilhelm, Alfredo Cabrera-Orefice, M. Lienhard Schmitz","doi":"10.1038/s41418-025-01532-5","DOIUrl":"https://doi.org/10.1038/s41418-025-01532-5","url":null,"abstract":"<p>As cancer cell specific rewiring of metabolic networks creates potential therapeutic opportunities, we conducted a synthetic lethal screen utilizing inhibitors of metabolic pathways. Simultaneous administration of (R)-GNE-140 and BMS-986205 (Linrodostat) preferentially halted proliferation of ovarian cancer cells, but not of their non-oncogenically transformed progenitor cells. While (R)-GNE-140 inhibits lactate dehydrogenase (LDH)A/B and thus effective glycolysis, BMS-986205, in addition to its known inhibitory activity on Indoleamine 2,3-dioxygenase (IDO1), also restricts oxidative phosphorylation (OXPHOS), as revealed here. BMS-986205, which is being tested in multiple Phase III clinical trials, inhibits the ubiquinone reduction site of respiratory complex I and thus compromises mitochondrial ATP production. The energetic catastrophe caused by simultaneous interference with glycolysis and OXPHOS resulted in either cell death or the induction of senescence in tumor cells, with the latter being eliminated by senolytics. The frequent synergy observed with combined inhibitor treatment was comprehensively confirmed through testing on tumor cell lines from the DepMap panel and on human colorectal cancer organoids. These experiments revealed highly synergistic activity of the compounds in a third of the tested tumor cell lines, correlating with alterations in genes with known roles in metabolic regulation and demonstrating the therapeutic potential of metabolic intervention.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"26 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144341112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms of immune cell death in immunosenescence","authors":"Joost Verduijn, Kelly Coutant, Mitchell E. Fane, Lorenzo Galluzzi","doi":"10.1038/s41418-025-01535-2","DOIUrl":"https://doi.org/10.1038/s41418-025-01535-2","url":null,"abstract":"<p>Along with organismal aging, multiple compartments of the immune system undergo a progressive functional degeneration that may contribute to – or at least allow for – disease, a scenario that is commonly known as “immunosenescence”. While not all immune cell populations suffer from organismal aging through similar mechanisms, immunosenescence appears to involve numerical alterations in specific immune cell types that – at least in some settings – result from the unscheduled activation of regulated cell death (RCD), often along with unbalanced hematopoietic output downstream of thymic involution and bone marrow defects. Here, we critically discuss core RCD mechanisms including apoptosis, necroptosis, ferroptosis, pyroptosis and NETosis as key regulators of global immune homeostasis in the context of immunosenescence.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"12 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144341027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial cells-derived SEMA3G suppresses glioblastoma stem cells by inducing c-Myc degradation","authors":"Peng-Xiang Min, Li-Li Feng, Yi-Xuan Zhang, Chen-Chen Jiang, Hong-Zhen Zhang, Yan Chen, Kohji Fukunaga, Fang Liu, Yu-Jie Zhang, Takuya Sasaki, Xu Qian, Katsuhisa Horimoto, Jian-Dong Jiang, Ying-Mei Lu, Feng Han","doi":"10.1038/s41418-025-01534-3","DOIUrl":"https://doi.org/10.1038/s41418-025-01534-3","url":null,"abstract":"<p>The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascular niche to maintain stemness. However, the effect of abnormal communication between endothelial cells (ECs) and GSCs on GBM progression remains unknown. Here, we reveal that ECs-derived SEMA3G, which is aberrantly expressed in GBM patients, impairs GSCs by inducing c-Myc degradation. SEMA3G activates NRP2/PLXNA1 in a paracrine manner, subsequently inducing the inactivation of Cdc42 and dissociation of Cdc42 and WWP2 in GSCs. Once released, WWP2 interacts with c-Myc and mediates c-Myc degradation via ubiquitination. Genetic deletion of <i>Sema3G</i> in ECs accelerates GBM growth, whereas <i>SEMA3G</i> overexpression or recombinant SEMA3G protein prolongs the survival of GBM bearing mice. These findings illustrate that ECs play an intrinsic inhibitory role in GSCs stemness via the SMEA3G-c-Myc distal regulation paradigm. Targeting SEMA3G signaling may have promising therapeutic benefits for GBM patients.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"45 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144311686","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Daniel Aberdam, the legacy of a mentor.","authors":"Huiqing Zhou, Bernard Attali, Neil Lagali, Ruby Shalom-Feuerstein","doi":"10.1038/s41418-025-01520-9","DOIUrl":"https://doi.org/10.1038/s41418-025-01520-9","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: EGFR inhibits TNF-α-mediated pathway by phosphorylating TNFR1 at tyrosine 360 and 401.","authors":"Young Woo Nam, June-Ha Shin, Seongmi Kim, Chi Hyun Hwang, Choong-Sil Lee, Gyuho Hwang, Hwa-Ryeon Kim, Jae-Seok Roe, Jaewhan Song","doi":"10.1038/s41418-024-01425-z","DOIUrl":"10.1038/s41418-024-01425-z","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":"1180"},"PeriodicalIF":13.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12162838/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142766513","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":"DNA damage response defects induced by the formation of TDP-43 and mutant FUS cytoplasmic inclusions and their pharmacological rescue","authors":"Stefania Modafferi, Stefania Farina, Francesca Esposito, Ornella Brandi, Michela Di Salvio, Ilaria Della Valle, Sara D’Uva, Eveljn Scarian, Giada Cicio, Adelaide Riccardi, Federica Pisati, Anna Garbelli, Tiziana Santini, Orietta Pansarasa, Mariangela Morlando, Nadia D’Ambrosi, Mauro Cozzolino, Gianluca Cestra, Fabrizio d’Adda di Fagagna, Ubaldo Gioia, Sofia Francia","doi":"10.1038/s41418-025-01530-7","DOIUrl":"https://doi.org/10.1038/s41418-025-01530-7","url":null,"abstract":"<p>Formation of cytoplasmic inclusions (CIs) of TDP-43 and FUS, along with DNA damage accumulation, is a hallmark of affected motor neurons in Amyotrophic Lateral Sclerosis (ALS). However, the impact of CIs on DNA damage response (DDR) and repair in this pathology remains unprobed. Here, we show that CIs of TDP-43 and FUS^P525L, co-localizing with stress granules, lead to a dysfunctional DDR activation associated with physical DNA breakage. Inhibition of the activity of the DDR kinase ATM, but not of ATR, abolishes DDR signaling, indicating that DNA double-strand breaks (DSBs) are the primary source of DDR activation. In addition, cells with TDP-43 and FUS^P525L CIs exhibit reduced DNA damage-induced RNA synthesis at DSBs. We previously showed that the two endoribonucleases DROSHA and DICER, also known to interact with TDP-43 and FUS during small RNA processing, contribute to DDR signaling at DSBs. Treatment with enoxacin, which stimulates DDR and repair by boosting the enzymatic activity of DICER, restores a proficient DDR and reduces DNA damage accumulation in cultured cells with CIs and in vivo in a murine model of ALS. In <i>Drosophila melanogaster</i>, Dicer-2 overexpression rescues TDP-43-mediated retinal degeneration. In summary, our results indicate that the harmful effects caused by TDP-43 and FUS CIs include genotoxic stress and that the pharmacological stimulation of the DNA damage signaling and repair counteracts it.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"26 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144164774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the BCKDK/BCLAF1/MYC/HK2 axis to alter aerobic glycolysis and overcome Trametinib resistance in lung cancer","authors":"Hao Wu, Jiajia Yang, Zixia Yang, Yawen Xiao, Ran Liu, Jing Jia, Xinrui Zhang, Yuting Zhang, Zheng Fu, Zhi Yao, Junqiang Lv","doi":"10.1038/s41418-025-01531-6","DOIUrl":"https://doi.org/10.1038/s41418-025-01531-6","url":null,"abstract":"<p>The protein branched-chain ketoacid dehydrogenase kinase (BCKDK), which regulates the metabolism of branched-chain amino acids, has recently been implicated in tumor progression. However, the role of BCKDK in lung cancer remains largely unexplored. In this study, we explored the mechanisms by which BCKDK influences lung cancer progression and contributes to drug resistance. By integrating single-cell RNA and bulk RNA sequencing data from lung cancer patients, we identified BCKDK as a novel gene related to malignant epithelial cells, involved in tumor initiation and associated with poor patient prognosis. Subsequently, through a series of molecular biology experiments, we demonstrated that BCKDK promotes aerobic glycolysis, Trametinib resistance, and tumor progression in lung cancer by upregulating MYC transcription. Mechanistically, BCKDK interacts with BCLAF1 to promote its phosphorylation at the serine 285 site. This modification facilitates BCLAF1 binding to the MYC promoter, thereby enhancing MYC transcription. Subsequently, elevated MYC levels upregulate hexokinase 2, promoting aerobic glycolysis and lung cancer progression. In addition, the elevated glycolysis product, lactate, promotes Trametinib resistance by upregulating the ABC transporters. Taken together, our data identify BCKDK as a novel regulator of aerobic glycolysis that promotes lung cancer progression and Trametinib resistance through the BCKDK/BCLAF1/MYC/HK2 axis. Targeting BCKDK in combination with Trametinib may offer a promising treatment for lung cancer.</p><figure><p>Graphical representation of the BCKDK/BCLAF1/MYC/HK2 axis and its role in Trametinib resistance and lung cancer progression. Created with BioRender.com.</p></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"4 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NDUFS3 promotes proliferation via glucose metabolism reprogramming inducing AMPK phosphorylating PRPS1 to increase the purine nucleotide synthesis in melanoma","authors":"Guohang Xiong, Fang Yun, Lu Jiang, Zihan Yi, Xiaojia Yi, Lijuan Yang, Xuedan Zhang, Xiaoyu Li, Zhe Yang, Qiao Zhang, Buqing Sai, Yingmin Kuang, Yuechun Zhu","doi":"10.1038/s41418-025-01525-4","DOIUrl":"https://doi.org/10.1038/s41418-025-01525-4","url":null,"abstract":"<p>NADH dehydrogenase [ubiquinone] iron-sulfur protein 3 (NDUFS3) is the core subunit of the respiratory chain complex I (CI). We found NDUFS3 were abnormally elevated in human melanoma and promoted melanoma proliferation. Furthermore, NDUFS3 could promote the oxidative phosphorylation (OXPHOS) and the pentose phosphate pathway (PPP), as well as attenuated glycolysis. As NDUFS3-mediated the metabolic changes of OXPHOS and glucose metabolism, melanoma cells produced more ATP, resulting in the inhibition of AMP kinase (AMPK). AMPK induced phosphoribosyl pyrophosphate synthetase1 (PRPS1) phosphorylation, which resulted in suppressed PRPS1 activity. Briefly, the NDUFS3-AMPK-PRPS1 signaling axis coupled OXPHOS, glucose metabolism, and purine nucleotide biosynthesis to regulate melanoma proliferation. Our study highlighted an unrecognized role for NDUFS3 in melanoma, which might be used as a potential therapeutic target for the treatment of this type of cancer.</p><figure><p>NDUFS3 regulating PRPS1 activity through AMPK to affect melanoma proliferation.</p></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"2 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144113537","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}