Cell Death Discovery最新文献

{"title":"CXCL12 alone is enough to Reprogram Normal Fibroblasts into Cancer-Associated Fibroblasts.","authors":"Zelong Ma, Diping Yu, Siqi Tan, Hao Li, Faxiao Zhou, Lei Qiu, Xiaoli Xie, Xiaoming Wu","doi":"10.1038/s41420-025-02420-0","DOIUrl":"https://doi.org/10.1038/s41420-025-02420-0","url":null,"abstract":"<p><p>Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment (TME), playing significant roles in regulating cancer progression. However, the underlying mechanism of CAFs activation remains elusive. In this study, we aim to investigates the mechanisms by which CAFs promote the conversion of normal fibroblasts (NFs) to CAFs in lung cancer, with a focus on the role of p53 mutations and the CXCL12/STAT3 signaling axis. We found that CAFs significantly induced NFs to acquire CAFs properties (called CEFs), including upregulation of α-SMA and Vimentin, enhanced proliferation and migration, and increased ability to promote lung cancer cell migration. In vivo, CEFs accelerated A549 xenograft growth and induced spontaneous lung metastasis. CXCL12 was identified as a key factor in NFs-to-CEFs conversion, with its expression positively correlated with CAFs markers in lung cancer. Further investigation confirmed that CXCL12 is sufficient to reprogram NFs into CAFs through the STAT3 pathway. Notably, inhibiting CXCL12 signaling and the STAT3 pathway reduced the conversion of NFs to CAFs, thereby hindering lung cancer progression progression both in vitro and in vivo. Our study reveals CAFs could promote the conversion of NFs to CAFs-like cells through the CXCL12/STAT3 axis, enhancing tumor growth and metastasis in lung cancer. Therefore, inhibition of the CXCL12/STAT3 axis is a promising strategy for the treatment of lung cancers and other CXCL12-dependent malignancies.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"156"},"PeriodicalIF":6.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metrnl protects intestinal barrier function by regulating tight junctions via the IKKβ/IκBα/NFκB/MLCK/MLC signaling pathway.","authors":"Zhi-Yong Li, Heng-Yu Luo, Fei Xu, Yao Xu, Chun-Hui Ma, Sai-Long Zhang, Sheng Xu, Yuan-Yuan Ma, Nan Li, Chao-Yu Miao","doi":"10.1038/s41420-025-02457-1","DOIUrl":"https://doi.org/10.1038/s41420-025-02457-1","url":null,"abstract":"<p><p>Meteorin-like (Metrnl), also known as Subfatin, IL-41, or Cometin, is a secreted protein predominantly expressed in the intestinal epithelium. The intestinal barrier, primarily consisting of epithelial cells connected by tight junctions, is essential for maintaining gut homeostasis by preventing harmful substances from entering the body. Despite Metrnl's high expression in the intestine, its role in barrier function remains unclear. In this study, we investigated Metrnl's role in intestinal barrier function using both loss-of-function (using global and intestinal epithelium-specific knockout mice) and gain-of-function (using intestinal epithelium-specific overexpression mice) approaches. Our findings showed that Metrnl deficiency disrupted tight junctions between enterocytes and exacerbated endotoxin-induced barrier dysfunction. Mechanistically, Metrnl deficiency triggered activation of the IKKβ/IκBα/NFκB signaling pathway, leading to increased MLCK expression and MLC phosphorylation. The NFκB inhibitor PDTC reversed this effect both in vivo and in vitro. Macrophages played an essential role in Metrnl's intestinal barrier protective effects during endotoxemia, but were not necessary in burn-induced barrier injury, suggesting potential differences in mechanism between these conditions. Notably, recombinant Metrnl protein administration protected against barrier dysfunction, and genetic overexpression of Metrnl in enterocytes preserved barrier function and alleviated DSS-induced colitis. These findings establish Metrnl as a key regulator of intestinal barrier integrity through the IKKβ/IκBα/NFκB/MLCK/MLC pathway, highlighting its potential therapeutic value in treating barrier dysfunction disorders. Intestinal barrier dysfunction triggers, such as endotoxin and severe burns, may induce the release of Metrnl from vascular endothelium. This leads to an increase in circulating Metrnl. Both circulating Metrnl and local Metrnl inhibit inflammation and the IKKβ/IκBα/NFκB/MLCK/MLC signaling pathway in enterocytes, thereby protecting tight junctions from disruption caused by endotoxin or burns.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"155"},"PeriodicalIF":6.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VANGL2 downregulates HINT1 to inhibit the ATM-p53 pathway and promote cisplatin resistance in small cell lung cancer.","authors":"Jiayi Xie, Huiying Liu, Chunqian Yang, Weitao Shen, Jian Zhang","doi":"10.1038/s41420-025-02424-w","DOIUrl":"https://doi.org/10.1038/s41420-025-02424-w","url":null,"abstract":"<p><p>Cisplatin is a first-line drug for the treatment of small cell lung cancer (SCLC). Although the majority of patients with SCLC initially respond to cisplatin therapy, cisplatin resistance readily develops, leading to tumor progression. Therefore, this study aims to elucidate the mechanisms underlying cisplatin resistance in SCLC. We found that VANGL2 is a poor prognostic factor and promotes cisplatin resistance in SCLC. Mechanistically, in cisplatin-resistant cells, VANGL2 overexpression leads to the autophagic degradation of HINT1. This reduction in HINT1 expression further reduces the phosphorylation of ATM and p53 induced by cisplatin-mediated DNA damage. The decreased phosphorylation of p53 inhibits downstream apoptotic pathways, thereby reducing cisplatin-induced apoptosis. In conclusion, VANGL2 regulates the ATM-p53 pathway-mediated apoptotic response of SCLC to cisplatin by downregulating HINT1, thereby promoting cisplatin resistance. Thus, VANGL2 may serve as a potential therapeutic target for reversing cisplatin resistance in SCLC patients.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"153"},"PeriodicalIF":6.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"L-asparaginase is a PAR2 N-terminal protease that unmasks the PAR2 tethered ligand.","authors":"Jung Kwon Lee, Karl Riabowol, Xidi Wang, Ki-Young Lee","doi":"10.1038/s41420-025-02467-z","DOIUrl":"10.1038/s41420-025-02467-z","url":null,"abstract":"<p><p>L-asparaginase is an indispensable chemotherapeutic drug for patients with acute lymphoblastic leukemia (aLL), a life-threatening lymphoid neoplasm and the prime cause of cancer death among children. Previously, we reported that L-asparaginase kills aLL cells via an excessive rise in [Ca²⁺]_i due to IP3R-mediated ER Ca²⁺ release followed by stimulation of the intrinsic apoptotic pathway (Blood, 133, 2222-2232). We also demonstrated that L-asparaginase triggers ER Ca²⁺ release by targeting the G-protein-coupled receptor (GPCR), protease-activated receptor 2 (PAR2) (Cell Death & Discovery, 10:366). However, how L-asparaginase stimulates PAR2 remains unknown. Here, we show that elastase, which can disarm trypsin-mediated PAR2 activation by cleaving a S₆₇-V₆₈ residue downstream of the tethered ligand (TL) and removing it from PAR2, abrogates L-asparaginase-induced ER Ca²⁺ release, indicating that L-asparaginase targets the TL-containing PAR2 N-terminal extracellular domain to induce ER Ca²⁺ release. Inactive forms (T₁₁₁V/K₁₈₄T or D₁₁₂T/K₁₈₄T) of L-asparaginase do not induce ER Ca²⁺ release in μ-opioid receptor 1 (µ-OR1)-knockdown aLL cells, suggesting that L-asparaginase action on PAR2 requires its enzymatic activity. Time-lapse confocal microscopy of cells expressing mRFP-hPAR2-eYFP and nanoluciferase (Nluc) reporter release assays of cells expressing Nluc-hPAR2-eYFP showed that L-asparaginase cleaves PAR2 at the N-terminal extracellular I₂₆-G₇₁ domain. Cleavage assay of a PAR2 N-terminal peptide by L-asparaginase and subsequent LC-MS/MS analysis show that L-asparaginase is a PAR2 protease that cleaves N₃₀-R₃₁ and R₃₁-S₃₂ residues, unmasking the PAR2 TL. Thus, our findings reveal for the first time the molecular mechanism through which L-asparaginase activates PAR2, leading to perturbation of intracellular Ca²⁺ homeostasis and aLL cell apoptosis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"152"},"PeriodicalIF":6.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: SENP1 promotes MCL pathogenesis through regulating JAK-STAT5 pathway and SOCS2 expression.","authors":"Yali Zhang, Yanni Ma, Guixian Wu, Mingling Xie, Chengxin Luo, Xiangtao Huang, Feng Tian, Jieping Chen, Xi Li","doi":"10.1038/s41420-025-02347-6","DOIUrl":"https://doi.org/10.1038/s41420-025-02347-6","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"154"},"PeriodicalIF":6.1,"publicationDate":"2025-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143810612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DRP1, fission and apoptosis.","authors":"Nan Wang, Xinwai Wang, Beiwu Lan, Yufei Gao, Yuanyuan Cai","doi":"10.1038/s41420-025-02458-0","DOIUrl":"10.1038/s41420-025-02458-0","url":null,"abstract":"<p><p>Mitochondrial fission is a critical physiological process in eukaryotic cells, participating in various vital activities such as mitosis, mitochondria quality control, and mitophagy. Recent studies have revealed a tight connection between mitochondrial fission and the mitochondrial metabolism, as well as apoptosis, which involves multiple cellular events and interactions between organelles. As a pivotal molecule in the process of mitochondrial fission, the function of DRP1 is regulated at multiple levels, including transcription, post-translational modifications. This review follows the guidelines for Human Gene Nomenclature and will focus on DRP1, discussing its activity regulation, its role in mitochondrial fission, and the relationship between mitochondrial fission and apoptosis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"150"},"PeriodicalIF":6.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E3 ligase Skp2-mediated stabilization of survivin contributes to radioresistance.","authors":"Shiming Tan, Ruirui Wang, Jinglin Fang, Ming Yi, Pengfei Guo, Shuangze Han, Xiaoying Li, Yu Gan, Jinzhuang Liao, Xinfang Yu, Wei Li","doi":"10.1038/s41420-025-02463-3","DOIUrl":"10.1038/s41420-025-02463-3","url":null,"abstract":"<p><p>Oral squamous cell carcinoma (OSCC) is a frequently occurring neck and head malignancy. Therapies for OSCC are improving, but radiotherapy resistance remains a major clinical challenge. Here, we found that the S-phase kinase-associated protein 2 (Skp2) is overexpressed in OSCC cells and tissues. Knockdown of Skp2 significantly increased the radiotherapy sensitivity of OSCC cells. Further potential mechanisms suggest that Skp2-deficient restoration of radiotherapy sensitivity in OSCC cells may induce intrinsic apoptosis through inhibition of the Akt/Wee1/CDK1 axis, which inhibits Survivin phosphorylation and promotes its ubiquitination and degradation by FBXL7. Clinicopathologic histological analysis showed that Skp2 was positively correlated with the expression of p-Akt and Survivin in OSCC tissues. Furthermore, knockdown or inhibition of Skp2 overcame the radiotherapy resistance of OSCC cells. In conclusion, our study demonstrated that targeting the Skp2-Survivin axis could serve as an attractive and promising potential therapeutic target for radiotherapy sensitization in OSCC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"151"},"PeriodicalIF":6.1,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143802624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PKM2-mediated metabolic reprogramming of microglia in neuroinflammation.","authors":"Qi Zhang, Sha-Sha Wang, Zhao Zhang, Shi-Feng Chu","doi":"10.1038/s41420-025-02453-5","DOIUrl":"10.1038/s41420-025-02453-5","url":null,"abstract":"<p><p>Microglia, the resident immune cells of the central nervous system, undergo metabolic reprogramming during neuroinflammation, playing a crucial role in the pathogenesis of neurological disorders such as Parkinson's disease. This review focuses on Pyruvate Kinase M2 (PKM2), a key glycolytic enzyme, and its impact on microglial metabolic reprogramming and subsequent neuroinflammation. We explore the regulatory mechanisms governing PKM2 activity, its influence on microglial activation and immune responses, and its contribution to the progression of various neurological diseases. Finally, we highlight the therapeutic potential of targeting PKM2 as a novel strategy for treating neuroinflammation-driven neurological disorders. This review provides insights into the molecular mechanisms of PKM2 in neuroinflammation, aiming to inform the development of future therapeutic interventions.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"149"},"PeriodicalIF":6.1,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794610","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The LTB4-BLT1 axis attenuates influenza-induced lung inflammation by suppressing NLRP3 activation.","authors":"Cheng Wei, Yitian Xu, Ying Zheng, Lizhe Hong, Chen Lyu, Haibo Li, Bin Cao","doi":"10.1038/s41420-025-02450-8","DOIUrl":"10.1038/s41420-025-02450-8","url":null,"abstract":"<p><p>The mortality associated with influenza A virus (IAV) infection typically results from excessive immune responses, leading to immunopathological lung damage and compromised pulmonary function. Various immunomodulators are seen beneficial when used in conjunction with direct anti-infection treatment. Leukotriene B4 (LTB4) is a derivative of arachidonic acid (AA) and has been shown to be advantageous for numerous infectious diseases, allergies, and autoimmune disorders. Nonetheless, the function of LTB4 in influenza infection remains unclear. This study demonstrates that LTB4 and its primary receptor BLT1, as opposed to the secondary receptor BLT2, act as a protective immune modulator during influenza infection in bone marrow-derived macrophages and mouse models. Mechanistically, LTB4 promotes K27-linked and K48-linked polyubiquitination of the NLRP3 protein at its K886 and K1023 sites via a cAMP/PKA-dependent pathway, which inhibits NLRP3 inflammasome assembly and thereby diminishes subsequent NLRP3 inflammasome activation. The consequent decline in the release of IL-1β and IL-18 leads to a reduction in inflammation caused by viral infection. Furthermore, the administration of a LTB4 treatment in a fatal IAV infection model can mitigate the excessive NLRP3 inflammasome activation and reduce IAV-induced severe pulmonary damage. These findings illustrate the protective function of LTB4 in fatal IAV infection by mitigating the severe inflammation induced by the virus.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"148"},"PeriodicalIF":6.1,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11973165/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuronal CDK5RAP3 deficiency leads to encephalo-dysplasia via upregulation of N-glycosylases and glycogen deposition.","authors":"Fanghui Chen, Minghui Xiang, Zhipeng Wang, Fan Yang, Junzhi Zhou, Zihan Deng, Susu Wang, Ping Li, Jieqi Tew, Wei Zhang, Honglin Li, Yong Teng, Xiaobin Zhu, Yafei Cai","doi":"10.1038/s41420-025-02414-y","DOIUrl":"10.1038/s41420-025-02414-y","url":null,"abstract":"<p><p>CDK5RAP3 is a binding protein of CDK5 activating proteins and also one of the key co-factors of the E3 enzyme in the UFMylation system. Several reports have implicated the involvement of CDK5 and other components of the UFMylation system in neuronal development and multiple psychiatric disorders. However, the precise role of CDK5RAP3 in neurons remains elusive. In this study, we generated CDK5RAP3 neuron-specific knockout mice (CDK5RAP^F/F: Nestin-Cre). CDK5RAP3 conditional knockout (CDK5RAP3 CKO) mice exhibited severe encephalo-dysplasia and a slower developmental trajectory compared to wild-type (WT) mice and succumbed to postnatal demise by day 14. Transcriptome sequencing unveiled that CDK5RAP3 deficiency affects synapse formation, transmembrane trafficking and physiological programs in the brain. Morphological analysis demonstrated that neuronal CDK5RAP3 deficiency leads to increased SLC17A6 and N-glycosylase (RPN1 and ALG2) protein expression, and while causing endoplasmic reticulum (ER) stress. In vitro experiments utilizing CDK5RAP3^F/F: ROSA26-ERT2Cre MEFs were conducted to elucidate similar mechanism following CDK5RAP3 deletion. Both in vivo and in vitro, CDK5RAP3 deficiency significantly increased the expression of N-glycosylases (RPN1 and ALG2), as well as the total amount of glycoproteins. CDK5RAP3 may potentially maintain a balance by enhancing the degradation of RPN1 and ALG2 through proteolytic degradation pathways and autophagy. This study underscores the indispensable role of CDK5RAP3 in neuronal development and sheds new light on drug discovery endeavors targeting early brain abnormalities.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"11 1","pages":"146"},"PeriodicalIF":6.1,"publicationDate":"2025-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11972371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143787986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}