Cell Death and Differentiation最新文献

{"title":"ABCC10-mediated cGAMP efflux drives cancer cell radiotherapy resistance","authors":"Zhengyang Zhang, Jie Gao, Xiang Liao, Zining Zhang, Xiongfeng Cao, Yi Gong, Wenlong Chen, Lirong Zhang, Hsiang-i Tsai, Dongqing Wang, Haitao Zhu","doi":"10.1038/s41418-025-01552-1","DOIUrl":"https://doi.org/10.1038/s41418-025-01552-1","url":null,"abstract":"<p>Although radiotherapy (RT) is used in more than 50% of cancer patients, the intrinsic radioresistance of cancer cells, characterized by metabolic adaptation, significantly limits its clinical efficacy. However, the mechanisms underlying RT resistance (RTR) remain incompletely understood. In this study, we used high-throughput metabolic CRISPR library screening and identified ABCC10 as a novel molecular contributor to RTR. Functional assays, including vesicle transport, molecular docking, and an enzyme-linked immunosorbent assay, confirmed that the R545 site of ABCC10 binds to and effluxes 2′3′-cyclic GMP–AMP (cGAMP) in an ATP-dependent manner. Mechanistically, RNA transcriptomics, along with overexpression and silencing experiments, demonstrated that ABCC10-mediated export of cGAMP suppresses the STING-TBK1-IRF3 signaling pathway. This efflux reduces RT-induced intercellular accumulation of reactive oxygen species and DNA damage. In vivo, a combination of RT and nilotinib, a potential ABCC10 inhibitor, synergistically inhibited tumor growth. In summary, we identified ABCC10 as a novel exporter of cGAMP in RTR. Our results highlight its potential role as a biomarker for predicting RT response and as a therapeutic target for overcoming RTR.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"728 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786741","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":"The role of plant metacaspases in cell death and survival","authors":"Marta Salas-Gómez, Nerea Ruiz-Solaní, Laia Armengot, Nuria S. Coll","doi":"10.1038/s41418-025-01555-y","DOIUrl":"https://doi.org/10.1038/s41418-025-01555-y","url":null,"abstract":"<p>In plants, metacaspases—cysteine proteases—have gained attention for their roles in programmed cell death (PCD). However, to date, their proteolytic activity has not been established as a direct executioner of PCD, analogous to caspases in animals. In this regard, the specific executioners of PCD remain to be identified in plants, leaving the process less well understood than in animals. More recently, metacaspases have also been recognized for their roles in cellular homeostasis. This perspective explores the pro-death and pro-survival roles of plant metacaspases in plant stress responses and development. Under abiotic stress conditions, such as heat, drought or high salinity, metacaspases help maintain protein homeostasis and mitigate damage by regulating processes like the unfolded protein response. In plant immunity, metacaspases have context-dependent pro-death or pro-survival roles. Pro-survival roles include cleavage and generation of immune peptides and regulating immune receptor stability as part of immunocondensates. They have also been shown to tightly regulate immunogenic cell death after pathogen attack, although their mode of action in this context remains elusive. Developmentally, metacaspases participate in key processes that involve PCD, like xylem differentiation and lateral root cap formation, where they help control cellular remodelling. Ultimately, metacaspases are emerging as multifunctional molecules crucial to cellular integrity, immunity, and development. Understanding the balance between cell death and survival pathways in plants is crucial, as it directly impacts crop resilience to environmental stresses and pathogens, ultimately influencing food security and our dependence on plant-based resources.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144786791","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":"Histone deacetylase 6 deacetylates and ubiquitinates ATG3 to regulate autophagy","authors":"Jiayu Yao, Ziyang Zhao, Yousheng Chen, Xuan Xu, Ying Yang, Weiying Yue, Xingjuan Shi","doi":"10.1038/s41418-025-01553-0","DOIUrl":"https://doi.org/10.1038/s41418-025-01553-0","url":null,"abstract":"<p>ATG3 (autophagy-related gene 3), an E2 like enzyme, plays a vital role in autophagy by regulating the lipidation modification of LC3 (microtubule-associated protein 1A/1B-light chain 3). Although the level of ATG3 can be reduced by the ubiquitin-proteasome pathway, the detailed mechanisms of this regulation remain elusive. Histone deacetylase 6 (HDAC6) is involved in multiple cellular activities by regulating acetylation of its substrates such as α-tubulin and cortactin. Here, we revealed a novel function of HDAC6 in autophagy regulation by mediating the post-translational modifications of ATG3. We found that HDAC6 interacts with ATG3 and deacetylates ATG3. In addition, HDAC6 acts its ubiquitin E3 ligase activity and ubiquitinates ATG3 at lysine 272, leading to ATG3 degradation. Intriguingly, lysine 272 of ATG3 is targeted for deacetylation as well as ubiquitination by HDAC6. Further study showed that HDAC6 participates in autophagy by mediating ATG3 degradation. Taken together, our findings uncover a novel role of HDAC6 in autophagy regulation by mediating the protein modification and degradation of ATG3.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"27 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747588","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 to: The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival.","authors":"R Kang, D Tang, N E Schapiro, K M Livesey, A Farkas, P Loughran, A Bierhaus, M T Lotze, H J Zeh","doi":"10.1038/s41418-025-01539-y","DOIUrl":"https://doi.org/10.1038/s41418-025-01539-y","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.7,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717649","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":"The USP1-WDR48 deubiquitinase complex functions as a molecular switch regulating tumor-associated macrophage activation and anti-tumor response","authors":"Dianwen Han, Lijuan Wang, Shan Jiang, Peng Su, Bing Chen, Wenjing Zhao, Tong Chen, Ning Zhang, Xiaolong Wang, Yiran Liang, Yaming Li, Chen Li, Xi Chen, Dan Luo, Qifeng Yang","doi":"10.1038/s41418-025-01548-x","DOIUrl":"https://doi.org/10.1038/s41418-025-01548-x","url":null,"abstract":"<p>M2-like tumor-associated macrophages (TAMs) are the main immunosuppressive cells infiltrating the tumor microenvironment (TME), the activation of which is essential for cancer progression and resistance promotion to immunotherapy. However, the regulatory mechanisms underlying TAM activation have not been fully elucidated. Utilizing a CRISPR-Cas9-based genetically engineered mouse model, we discovered that USP1^fl/flLyz2^cre/+ and WDR48^fl/flLyz2^cre/+ mice exhibited decreased tumor formation and lung metastasis. Mechanistically, the USP1-WDR48 deubiquitinase complex regulated M2-TAM activation and infiltration in the TME by modulating DDX3X ubiquitination. Specifically, this complex interacted with the N-terminal RecA-like domain 1 of DDX3X, leading to K48-linked deubiquitination and stabilization of DDX3X. Then, DDX3X promoted the translation of signaling molecules Jak1 and Rac1 via its RNA helicase activity, activating the Jak1-Stat3/6 and Rac1-Akt pathways to drive M2-TAM activation. Furthermore, combined inhibition of the USP1/WDR48 and CD47/SIRPα signaling pathways showed synergistic antitumor effects in immunocompetent mice. Notably, USP1 protein expression in tumor stromal tissues independently predicts prognosis in breast cancer patients. These findings indicated the role of the USP1-WDR48 complex as a critical molecular switch controlling TAM activation, presenting novel and promising targets for breast cancer treatment.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"67 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701844","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":"KRAS mutation increases histone H3 lysine 9 lactylation (H3K9la) to promote colorectal cancer progression by facilitating cholesterol transporter GRAMD1A expression","authors":"Chi Zhang, Runfeng Yu, Senmao Li, Ming Yuan, Tuo Hu, Jiaqi Liu, Haoxian Ke, Shubiao Ye, Jihye Yun, Junfeng Huang, Guanzhan Liang, Shaopeng Chen, Xianrui Wu, Ping Lan","doi":"10.1038/s41418-025-01533-4","DOIUrl":"https://doi.org/10.1038/s41418-025-01533-4","url":null,"abstract":"<p>Histone lactylation is a novel epigenetic modification derived from lactate, but its role and mechanism in KRAS mutant colorectal cancer (CRC) progression remains to be fully elucidated. In this study, we first showed that mutant KRAS increased H3 lysine 9 lactylation (H3K9la) to promote CRC progression. We found that KRAS-mutant CRC tissues and cell lines exhibited higher lactylation and H3K9la levels compared to KRAS wild-type counterparts, driven by increased intracellular lactate. Elevated lactylation and H3K9la levels were associated with poor prognosis and advanced clinical stages. Inhibition of lactylation and H3K9la suppressed proliferation and migration of CRC cells. Mechanistically, mutant KRAS upregulated GRAMD1A expression by elevating H3K9la levels to increase chromatin accessibility. And increased GRAMD1A facilitated cholesterol metabolism to promote CRC growth and metastasis. Targeted inhibition of H3K9la or GRAMD1A reduced tumor growth in CRC patient-derived xenografts (PDX) models. Our study uncovered the critical role of H3K9la as a novel epigenetic modification in KRAS mutant CRC progression, suggesting H3K9la and its downstream gene GRAMD1A as promising targets for therapeutic intervention in KRAS mutant CRC and potential biomarkers for the prognosis of CRC patients.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"31 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144694068","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":"The roles of mutant p53 in reprogramming and inflammation in breast cancers","authors":"Shivaani Kummar, Marc Fellous, Arnold J. Levine","doi":"10.1038/s41418-025-01549-w","DOIUrl":"https://doi.org/10.1038/s41418-025-01549-w","url":null,"abstract":"<p>Rezatapopt is an investigational small molecule p53 reactivator that binds specifically to the Y220C-mutant p53 protein without interacting with wild-type or other mutant p53 proteins. Upon binding, rezatapopt stabilizes the Y220C-mutant p53 protein in the wild-type conformation, reactivating p53 functions. The Phase 1 PYNNACLE trial assessed rezatapopt in solid tumors. One study participant with triple-negative breast cancer experiencing severe inflammation of the skin overlying the breast and left arm edema saw inflammation improve within 1 week of receiving rezatapopt and completely resolve shortly after. After 6 weeks of treatment, tumor volume had reduced 41%. The patient remains on study, with continued resolution of the skin inflammation and reduced tumor burden for greater than 24 months. There are several wild type Tp53 regulated pathways that could play a role in reversing the inflammatory response and tumor growth observed in this patient case. This perspective explores the signal transduction pathways involved in this cancer mediated inflammation and the extensive reduction of detectable tumor tissue.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"4 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144685171","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":"Ripk1 is critical for preserving effector regulatory T cells and the suppressive transcriptional program in regulatory T cells","authors":"Carlos Plaza-Sirvent, Hannah Sturm, Maximilian K. Nocke, Fatemeh Ghorbani, Clara Bessen, Marina C. Greweling-Pils, Stefan Floess, Jana Niemz, Jelle Huysentruyt, Peter Tougaard, Jochen Huehn, Robert Geffers, Daniel Todt, Peter Vandenabeele, Ingo Schmitz","doi":"10.1038/s41418-025-01550-3","DOIUrl":"https://doi.org/10.1038/s41418-025-01550-3","url":null,"abstract":"<p>Ripk1 plays an important role as a regulator of programmed cell death processes such as apoptosis and necroptosis and is involved in initiating pro-inflammatory NF-κB signaling. Immune tolerance depends on the proper function and homeostasis of regulatory T (Treg) cells. Here, we show that specific ablation of Ripk1 in Treg cells leads to systemically reduced Treg cell numbers resulting in spontaneous whole-body pathology. Using chimeric mice that allowed us to study Treg cells in the absence of inflammatory conditions, we observed a competitive disadvantage in vivo of Ripk1-deficient compared to Ripk1-proficient Treg cells. Furthermore, single-cell RNA sequencing revealed that Ripk1 is required for the maintenance of the effector Treg cell transcriptional signature, which is essential to prevent immune dysregulation. To overcome the limitation of low cell numbers in the chimeric mice, we isolated Treg cells from mice, in which Ripk1 could be deleted in a tamoxifen-inducible manner. Despite the strong reduction detected in Ripk1-deficient Treg cells of the chimeric mice, we did not observe impaired viability by the sole absence of Ripk1 in Treg cells from the inducible system. Of note, we observed reduced viability of activated Ripk1-deficient Treg cells in the presence of TNF. Together, these findings highlight the fundamental role of Ripk1 in maintaining immune homeostasis by preserving the highly suppressive effector Treg cells.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"17 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677244","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 KAT8 alleviates self-RNA-driven skin inflammation by modulating histone H4 lysine 16 acetylation in psoriasis","authors":"Yan Xiang, Yuyu Jiang, Zeting Wang, Xiaohui Wang, Lijie Ma, Yingying Ding, Bing Rui, Chunyan Zhao, Xiangyu Li, Mingyuan Xu, Yunkai Zhang, Zhenzhen Zhan, Xingguang Liu","doi":"10.1038/s41418-025-01547-y","DOIUrl":"https://doi.org/10.1038/s41418-025-01547-y","url":null,"abstract":"<p>Psoriasis is a persistent inflammatory skin disease characterized by the adverse infiltration of inflammatory cells and epidermal hyperplasia. Self-RNA is the most abundant damage-associated molecular pattern (DAMP) in psoriasis tissues, which triggers and amplifies inflammatory responses through TLR7 pathway. However, the pathogenic effects of self-RNA on immune cell activation and chemotaxis during psoriasis and the underlying mechanisms remain largely unknown. Epigenetic modifications are widely acknowledged to link the environmental signals to gene expression in various immune cells, whose dysfunction tends to cause or worsen various inflammatory diseases. Through a comprehensive analysis of histone modifications in lesional skin from both psoriasis patients and mice, the significantly increased level of histone acetylation at H4 lysine 16 (H4K16ac) in macrophages was found, which was positively correlated with the accumulation of self-RNA in the dermis and psoriasis pathology. Further studies showed that lysine acetyltransferase 8 (KAT8) was responsible for self-RNA-driven H4K16ac modification and psoriasis-associated pathogenic chemokine expression in macrophages of lesional skin. Mechanistically, KAT8 was selectively recruited to the gene promoters of pathogenic chemokines including <i>Cxcl2</i> and <i>Ccl3</i> through interaction with AP-1 transcription complex. The auto-acetylation of KAT8 enhanced its acetyltransferase activity. KAT8-mediated H4K16ac modification at these chemokine promoters, coupling with increased chromatin accessibility, facilitated the production and secretion of pro-inflammatory chemokines CXCL2 and CCL3 for neutrophil chemotaxis, neutrophil extracellular traps (NETs) formation and aggravated inflammatory damage in psoriasis. KAT8 deficiency in macrophages or pharmacological inhibition restricted the secretion of macrophage-derived pro-inflammatory chemokines and ameliorated TLR7-dependent tissue inflammatory injury in experimental psoriasis and arthritis model. Taken together, our finding provides new insight into the role of epigenetic modification in self-RNA/TLR7 pathway-dependent immune cell activation and chemotaxis during psoriasis, which proposes the promising therapeutic strategy to control the inflammatory damage and psoriatic skin dysfunction by targeting KAT8 and KAT8-mediated H4K16ac modification in dermis macrophages.</p><figure></figure>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"68 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144677240","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":"FMRP regulation of STAT3-MYC signaling is critical for adult hippocampal neurogenesis and cognitive flexibility","authors":"Yue Li, Wenxin Ma, Ruishuang Ma, Shuang Wang, Xu Liu, Xiaomeng Guo, Wenhua Li, Xiaopeng Chen, Yuan-Lu Cui, He Song","doi":"10.1038/s41418-025-01546-z","DOIUrl":"https://doi.org/10.1038/s41418-025-01546-z","url":null,"abstract":"<p>Fragile X syndrome (FXS), the most common form of inherited intellectual disability, results from a loss of fragile X mental retardation protein (FMRP), an RNA-binding protein whose deficiency impacts many targeted mRNA and brain functions. However, how these FMRP targets contribute to the pathogenesis of FXS is not fully understood, and effective treatment is lacking. Here, we identify signal transducer and activator of transcription 3 (STAT3) as a target of FMRP in adult hippocampal neural stem cells (NSCs). FMRP regulates <i>Stat3</i> mRNA stability and protein translation, and loss of FMRP results in elevated <i>Stat3</i> mRNA and protein, leading to aberrant neurogenesis and impaired dendritic maturation in adult NSCs and developing neurons. Activation of <i>Stat3</i> in adult mouse hippocampal NSCs impairs cognitive flexibility. We show that STAT3 phosphorylation specifically binds to MYC, which is essential for adult hippocampal neurogenesis. Both genetic reduction of STAT3 and pharmacological treatment with artesunate, the first-line drug for treating malaria worldwide, rescue neurogenic and cognitive deficits in FMRP-deficient mice. Our work reveals a potential regulatory role for FMRP and STAT3-MYC signaling pathway in adult neurogenesis and cognitive flexibility, and provides a potential novel therapeutic strategy for treating adult FXS patients.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"109 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144664439","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}