Cell Death and Differentiation最新文献

{"title":"DDX3X regulates DNA repair pathway choice at double-strand breaks via RNA-DNA hybrid formation","authors":"Wei Wu,Mengjiao Lan,Juan Zhang,Huankun Sun,Ying Liu,Pumin Zhang","doi":"10.1038/s41418-026-01873-9","DOIUrl":"https://doi.org/10.1038/s41418-026-01873-9","url":null,"abstract":"Abstract DNA Double-strand breaks (DSBs) are amongst the most cytotoxic DNA lesions. During the processing of DSBs, so-called Break-Induced RNA-DNA Hybrids (BIRDHs) are generated to promote timely DSB repair. Here, we identify the DEAD-box helicase DDX3X as a positive regulator of BIRDHs and a key factor in facilitating DSB repair via homologous recombination (HR). We demonstrate that DDX3X promotes BIRDH formation by inhibiting CST (CTC1, STN1, TEN1)-Polα fill-in synthesis, through limiting 53BP1 accumulation at DSBs in a Drosha-dependent manner. Notably, depletion of DDX3X impairs both BIRDH and BRCA1 focus formation, while disabling CST-Polα mediated fill-in synthesis in DDX3X-deficient cells restores these events. This suggests a competitive interplay between BIRDH formation and fill-in synthesis that influences DNA repair pathway choice. Consistent with a role in HR, DDX3X depletion sensitizes tumor cells to cisplatin in vitro and in vivo. We conclude that DDX3X promotes genome maintenance and cell viability following DSB formation through regulation of BIRDHs.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"7 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149049507","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":"Hepatitis B virus protein X promotes survival and loss of hepatocyte identity in a differentiated human liver organoid system.","authors":"Xingyu Fan, Bram Torenvliet, Alexandros Galaras, Tanvir Hossain, Lincon Hasda, Martin E van Royen, Helmuth Gehart, Lili Zhao, Eleni Katsoni, Tsung Wai Kan, Panagiotis Moulos, Shringar Rao, Farzin Pourfarzad, Javier Frias Aldeguer, Sylvia F Boj, Pantelis Hatzis, Robert-Jan Palstra, Tokameh Mahmoudi","doi":"10.1038/s41418-026-01877-5","DOIUrl":"https://doi.org/10.1038/s41418-026-01877-5","url":null,"abstract":"<p><p>Hepatitis B virus (HBV) drives hepatocellular carcinoma in part through the activity of its X protein (HBx), yet the mechanisms by which HBx alters hepatocyte function remain incompletely understood. Progress has been limited by the lack of relevant human models that support controlled HBx expression in mature hepatocytes. To address this limitation, here, we use an improved hepatocyte-like organoid (HLO) platform that supports enhanced hepatocyte maturation to investigate HBx function in a differentiated hepatocyte context. Adult stem cell-derived HLOs were differentiated using an optimized protocol to generate hepatocyte-like cells with enhanced maturation and transcriptional similarity to primary liver tissue. HBx function was interrogated using both cognate promoter-driven expression and doxycycline-inducible systems across multiple donor-derived organoid lines. Transcriptomic, pathway, and single-cell imaging analyses were performed to assess the impact of HBx expression on hepatocytes. HBx expression consistently suppressed apoptosis-associated transcripts and reduced expression of core hepatocyte identity genes, including CYP3A4. Pathway analysis revealed downregulation of liver-specific functions, including metabolism, detoxification, complement, and coagulation. At the single-cell level, higher HBx expression was associated with reduced caspase 3/7 activation following apoptotic challenge and decreased hepatocyte marker expression. Functionally, the expression of HBx increased resistance to apoptosis and enhanced the ability of differentiated hepatocyte-like cells to revert to a proliferative state. HBx expression in differentiated human liver organoids reduces apoptosis and impairs hepatocyte identity, consistently across donors and expression systems. Together, these findings support a model in which HBx promotes a survival-permissive state of reduced hepatocyte differentiation. This state may contribute to early HBV-driven tumorigenesis. This HLO platform provides a relevant system to dissect HBV-host interactions and reveals a mechanism by which HBV may prime the liver for malignant transformation. IMPACT AND IMPLICATIONS: Understanding how HBV promotes hepatocellular carcinoma remains a critical challenge, partly due to the lack of physiologically relevant human derived model systems to study HBx function. Using a differentiated adult human liver organoid system, we show that HBx simultaneously suppresses apoptosis and reduces hepatocyte differentiation, providing a mechanistic framework for how HBV may prime hepatocytes for malignant transformation. These findings are particularly relevant for researchers studying HBV pathogenesis and liver cancer, as well as for clinicians aiming to better understand early disease progression. While further validation in more complex multicellular systems is needed, this platform can support the identification of HBx-targeted therapeutic strategies and guide the development of improved adult","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149036645","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":"NLRX1 is a critical neutrophil checkpoint modulating ferroptosis and suppressing NETosis to attenuate joint damage in arthritis.","authors":"Zhuan Feng, Rongrong Liu, Jialu Hou, Zhaohui Zheng, Xiang Zhang, Xianghui Fu, Fei Huo, Hai Zhang, Yaxin Ding, Feiyang Meng, Danni Sun, Qian He, Bo Shi, Zhi-Nan Chen, Ping Zhu, Jiao Wu","doi":"10.1038/s41418-026-01875-7","DOIUrl":"https://doi.org/10.1038/s41418-026-01875-7","url":null,"abstract":"<p><p>Neutrophil extracellular traps (NETs) are key drivers of inflammation and tissue damage in rheumatoid arthritis (RA), yet the mechanisms that restrain NETs overproduction remain unclear. Here, we identify the mitochondrial NOD-like receptor NLRX1 as a critical checkpoint limiting NETs production. The expression of NLRX1 is dysregulated in RA patients. NLRX1 deficiency leads to a profound expansion of the neutrophil population, and neutrophil-specific NLRX1 deficiency results in broad production of cytokines, chemokines, autoantibodies and complement accompanied by markedly accelerated arthritis, exaggerated NETs formation, and enhanced joint damage. Single-cell RNA sequencing reveals that NLRX1 restrains a Padi4-high neutrophil population that is central to NETosis. Mechanistically, NLRX1 deficiency promotes sustained TRAF6-NF-κB signaling and activates the NRF2-mediated oxidative defense pathway, which confers ferroptosis resistance to extend neutrophil lifespan and provides a prolonged temporal window for continuous NETs formation. NLRX1-knockdown cells exhibit increased NETs release, with a more ordered periodic distribution of myeloperoxidase (MPO) along the citrullinated histone H3 (CitH3)-decorated DNA backbone forming the typical 'beads-on-a-string' pattern, suggesting enhanced structural organization of NETs. NETs, known to directly degrade bone matrix through proteolytic enzymes, also promote TNFα production, with the cytokine enriched on NETs structures. TNFα in turn stimulates synovial macrophages to express the pro-osteoclastic factor RANKL, thereby fueling bone destruction. Pharmacological activation of the NLRX1 checkpoint attenuates osteoclast differentiation and joint damage. Collectively, these findings unveil the new role of NLRX1 in regulating neutrophil ferroptosis and NETs production and its potential as a therapeutic target for mitigating cartilage and bone damage in RA.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149029982","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":"Ubiquitination-mediated degradation of NLRX1 drives metabolic vulnerability and accelerates intervertebral disc degeneration","authors":"Zhi Du,Di Wu,Hanpeng Xu,Huaizhen Liang,Dingchao Zhu,Shuchang Peng,Bide Tong,Jie Lei,Xingyu Zhou,Hongchuan Wang,Yifan Du,Zixuan Ou,Junyu Wei,Xinyu Li,Rui Shi,Zhengdong Zhang,Bingjin Wang,Kun Wang,Xiaobo Feng,Cao Yang,Yu Song","doi":"10.1038/s41418-026-01864-w","DOIUrl":"https://doi.org/10.1038/s41418-026-01864-w","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"27 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149021280","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 expanding MDM2 universe.","authors":"Kurt Engeland","doi":"10.1038/s41418-026-01879-3","DOIUrl":"https://doi.org/10.1038/s41418-026-01879-3","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030038","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":"VMP1 restricts STING trafficking and activation through controlling CDIPT recruitment to ER membrane curvature","authors":"Chen Zhou,Dongsheng Bai,Jiawei Zhao,HongJie Yin,Jiaying Du,Chunyang Gu,Yuxiang Wang,Binyan Lin,Na Lu,Yue Zhao","doi":"10.1038/s41418-026-01861-z","DOIUrl":"https://doi.org/10.1038/s41418-026-01861-z","url":null,"abstract":"","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"2 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149021281","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":"Convergent TBK1 loss of function drives gasdermin E dependent pyroptosis and motor neuron degeneration across ALS genotypes","authors":"Zihan Qi, Xuehe Liu, Lu Geng, Xiaoni Liu, Siqi Dong, Jiatong Li, Wenyi Hua, Yifan Deng, Suomei Lai, Yuhao Wang, Yuhong Xia, Yuyun Han, Dongqing Zhu, Xiang Zhang, Jinsong Li, Jixi Li, Xiangjun Chen","doi":"10.1038/s41418-026-01874-8","DOIUrl":"https://doi.org/10.1038/s41418-026-01874-8","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of upper and lower motor neurons, yet it is unknown whether diverse genetic risks converge on a shared pathogenic pathway. Here we identify a common mechanism linking TBK1 insufficiency to inflammatory cell death across distinct ALS genotypes. Whole-exome sequencing of 8 familial ALS patients revealed that 3 of them carried pathogenic variants, namely TBK1 (R573H), TDP-43 (G298V)/GARS (I44M)/SETX (L1304W), or SOD1 (G94R)/SQSTM1 (G262R). Motor neurons differentiated from patient iPSCs, despite their different mutations, consistently exhibited axonal and neurite shortening, reduced TBK1 activity, increased phosphorylated TDP-43 with cytoplasmic aggregation, and co-assembly of caspase-8/7 with the pyroptosis executor gasdermin E (GSDME). Neuroinflammatory stimulation further enhanced caspase-8/7 and GSDME cleavage, increased RIPK1 phosphorylation and suppressed TBK1 activation in patient-derived motor neurons, whereas TBK1 knockdown in SH-SY5Y cells recapitulated these phenotypes. Furthermore, a generated humanized TBK1 R573H knock-in mouse developed progressive motor deficits accompanied by spinal motor-neuron loss, neuroinflammation, and TDP-43 pathology. In these mice, LPS challenge produced increased cleavage of GSDME and caspase-7, along with a marked upregulation of p-TDP-43 expression in vulnerable neurons. Together, these data identify TBK1 loss of function as an upstream driver of a caspase-8/7-GSDME pyroptotic program in motor neurons and provide a mechanistic bridge between neuroinflammation, TDP-43 proteinopathy, and neurodegeneration. Targeting the TBK1-caspase-GSDME axis may offer a tractable strategy for disease modification in ALS.","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":"9 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149010457","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":"ADORA1 inhibition suppresses colon cancer development via hippo tumor suppressor pathway.","authors":"Zhongbo Li, Zhihao Liu, Xiaobo Zhang, Zhuocong Bao, Xiujie Cui, Xin Li, Jiayao Cui, Fangyu Shen, Yan Zhou, Pengzhao Song, Lin Ma, He Li, Hanxue Zhang, Haidi Hu, Ting Zhuang, Xiaodong Tan, Jian Zhu","doi":"10.1038/s41418-026-01860-0","DOIUrl":"https://doi.org/10.1038/s41418-026-01860-0","url":null,"abstract":"<p><p>Coffee is one of the most commonly consumed beverages in daily life, with caffeine being the major psychoactive component that acts against fatigue and drowsiness. Epidemiological studies have demonstrated the protective effect of coffee intake on colon cancer risk, recurrence and overall survival, but the detailed mechanisms are unclear. In this study, we identified an adenosine receptor (ADORA) as an important upstream receptor for the Hippo/YAP axis and found that caffeine competitively blocked the activation of ADORA, which subsequently inhibited colon cancer carcinogenesis and progression. Caffeine blocked the activation of ADORA1 and then promoted YAP phosphorylation and deactivation via the Gαi-cAMP/PKA-LATS axis. Interestingly, YAP could bind to the promoter region of ADORA1 and facilitate its transcription, resulting in the formation of a positive feedback loop between Hippo signalling and the adenosine receptor pathway. Our study revealed a novel positive feedback loop between the Hippo/YAP axis and adenosine signalling in colon cancer progression, while the tumour-suppressive function of caffeine provides more guidance for lifestyle intervention for cancer prevention and therapeutics.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149007733","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":"PGC1α-mediated upregulation of PHD2 represses HIF-signaling, limiting prostate cancer progression.","authors":"Maider Fagoaga-Eugui, Natalia Martin-Martin, Amaia Zabala-Letona, Oihana Iriondo, Ana Talamillo, Lorea Valcarcel-Jimenez, Encarnación Pérez-Andrés, Onintza Carlivaris, Saioa Garcia-Longarte, Ferran Medina-Jover, Alice Macchia, Francesc Viñals, Veronica Torrano, Arkaitz Carracedo, Edurne Berra","doi":"10.1038/s41418-026-01858-8","DOIUrl":"https://doi.org/10.1038/s41418-026-01858-8","url":null,"abstract":"<p><p>PPARγ coactivator 1 alpha (PGC1α) is a master transcriptional coregulator of metabolism, and its activity mirrors many of the effects of hypoxia signaling in prostate cancer (PCa). Whereas PGC1α restrains PCa progression through its association with the estrogen-related receptor alpha (ERRα) and is a predictor of better patient outcome, hypoxia signaling is associated with poor prognosis. However, their interplay in PCa remains poorly understood. Here we show that the PGC1α/ERRα complex reduces the protein levels of Hypoxia Inducible transcription Factor alpha (HIFα). Moreover, loss of PGC1α is associated with the establishment of an autocrine pseudohypoxic state. Mechanistically, the transcriptional complex formed by PGC1α and ERRα binds to the EGLN1 promoter, induces PHD2 expression, and triggers canonical HIFα proteasomal degradation. This mechanism is oxygen-dependent and thus is prevented under severe hypoxia. Importantly, this regulatory axis provides a new component to the tumor-suppressive activity of the PGC1α/ERRα complex. Specifically, EGLN1 silencing partially reverts PGC1α-mediated PCa tumor suppressive properties both in cellulo and in vivo. Our findings are reinforced by a positive correlation between PGC1α/ERRα activity and EGLN1 expression levels in human PCa datasets. Altogether, these results support that PHD2-regulated degradation of HIFα contributes to PGC1α/ERRα-mediated PCa suppression.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148988243","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":"ATP synthase subunits e and g are essential for Ca²⁺ homeostasis and development in Drosophila melanogaster independent of oxidative phosphorylation.","authors":"Elena Frigo, Manuela Santalla, Michele Brischigliaro, Federica Boscolo Nata, Ludovica Tommasin, Michela Rossini, Denis Komarov, Stefania Ferro, Diana Pendin, Oriano Marin, Rodolfo Costa, Michela Carraro, Paolo Bernardi","doi":"10.1038/s41418-026-01869-5","DOIUrl":"https://doi.org/10.1038/s41418-026-01869-5","url":null,"abstract":"<p><p>Beyond its roles in ATP production and shaping cristae architecture, mitochondrial ATP synthase has been implicated in generating the permeability transition pore (PTP), a Ca²⁺-activated, high-conductance channel that leads to matrix swelling and cell death in mammalian cells. In Drosophila melanogaster, the PTP homolog rather forms a selective Ca²⁺-induced Ca²⁺-release (CICR) channel whose physiological relevance at the organism level remains poorly understood. Here, we down-regulated Drosophila subunits e and g, which are essential for PTP formation in yeast and mammalian cells. Ubiquitous down-regulation of either subunit caused larval developmental arrest, whereas tissue-specific suppression in muscle or neurons led to severe locomotor impairment. Dimerization was markedly reduced, altering mitochondrial ultrastructure while leaving respiratory capacity largely preserved. Strikingly, mitochondria from both knockdown animals accumulated larger Ca²⁺ loads, consistent with an impaired CICR. This was accompanied by near-complete loss of ecdysone, the Ca²⁺-dependent master hormone of metamorphosis. Neuron-specific knockdown flies displayed defective mitochondrial Ca²⁺ efflux and altered synaptic organization at the neuromuscular junction. Altogether, our findings establish that ATP synthase functions as a CICR channel controlling Ca²⁺ homeostasis, endocrine signaling and development in Drosophila.</p>","PeriodicalId":9731,"journal":{"name":"Cell Death and Differentiation","volume":" ","pages":""},"PeriodicalIF":13.6,"publicationDate":"2026-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148975804","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}