Rafael Medina-Guzmán, Bazhena Bahatyrevich-Kharitonik, Marie-Kim St-Pierre, Sara Márquez-Pérez, Elena Gavilán, Cristóbal Coronel-Guisado, Alicia Flores-Cortes, Rodrigo García-Valiente, Sandro Argüelles, Edel Kavanagh, Yiyi Yang, Tomas Deierborg, José Luis Venero, Cristina González-Aguilera, Bertrand Joseph, Miguel Ángel Burguillos
{"title":"Caspase-3 regulates RNA splicing and mitochondrial dynamics in microglia during Parkinson's disease.","authors":"Rafael Medina-Guzmán, Bazhena Bahatyrevich-Kharitonik, Marie-Kim St-Pierre, Sara Márquez-Pérez, Elena Gavilán, Cristóbal Coronel-Guisado, Alicia Flores-Cortes, Rodrigo García-Valiente, Sandro Argüelles, Edel Kavanagh, Yiyi Yang, Tomas Deierborg, José Luis Venero, Cristina González-Aguilera, Bertrand Joseph, Miguel Ángel Burguillos","doi":"10.1038/s41419-026-09141-x","DOIUrl":"10.1038/s41419-026-09141-x","url":null,"abstract":"<p><p>Caspase-3, a cysteine-aspartic protease canonically known for its role in apoptotic cell death, has been implicated in several non-apoptotic functions, particularly in microglia, the brain-resident macrophages. These novel functions appear to depend on distinct levels of caspase-3 activation; however, the role of basal caspase-3 activity remains unclear. Here, we show that basal caspase-3 regulates RNA splicing in microglia, and its deficiency in a Parkinson´s disease (PD) model leads to splicing dysregulation. Loss of basal caspase-3 activity also increases double-stranded RNA (dsRNA) accumulation, inducing a type I interferon response. Additionally, caspase-3 deficiency impairs mitochondrial respiration, reduces ATP production, and causes sex-specific mitochondrial abnormalities, predominantly in female microglia. Together, our findings uncover a non-apoptotic, homeostatic role for basal caspase-3 activity in microglia. Its disruption, such as in PD, may drive key molecular features of neuroinflammation and neurodegeneration, positioning caspase-3 as a critical regulator of microglial function in health and disease.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13614962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058643","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":"The KAT8-CDK1 K33 acetylation axis drives doxorubicin resistance by suppressing ferroptosis and apoptosis in breast cancer.","authors":"Qingzhi Zhao, Qixian Zou, Jinmeng Chu, Yizhen Wang, Tiantian Xu, Haoqing Dou, Chengyu Cai, Na Zhang, Fei Wang, Yin Gao, Yong Cai, Bing Liang, Jingji Jin","doi":"10.1038/s41419-026-09162-6","DOIUrl":"10.1038/s41419-026-09162-6","url":null,"abstract":"<p><p>Doxorubicin (Dox) resistance severely limits therapeutic efficacy in breast cancer, yet the epigenetic mechanisms linking cell-cycle control to therapy-induced cell death remain unclear. Here, we identify the histone acetyltransferase KAT8 as a critical driver of Dox resistance. Transcriptomic analysis of neoadjuvant cohorts revealed elevated KAT8 expression in residual disease (RD) tumors, which was validated in an independent cohort of 95 patients. High KAT8 levels correlated with poor therapeutic response. Mechanistically, KAT8 directly acetylated CDK1 at lysine 33 (K33) in Dox-resistant MCF-7/ADR and MDA-MB-231/ADR cells. K33 acetylation sustained CDK1 phosphorylation at T14, Y15, and T161, maintaining kinase activity under chemotherapeutic stress. Disruption of KAT8, either by genetic silencing or pharmacological inhibition with MG149, reduced CDK1 activation, increased mitochondrial depolarization and oxidative stress, and restored Dox sensitivity. Functionally, KAT8-dependent CDK1 K33 acetylation suppressed both apoptosis and ferroptosis, two principal Dox-induced cell death pathways. Re-expression of wild-type CDK1, but not the acetylation-deficient K33R mutant, rescued chemoresistance. In vivo, MG149 co-treatment or expression of CDK1-K33R significantly enhanced Dox-mediated tumor suppression in xenograft models without overt toxicity. Together, these findings establish KAT8-dependent CDK1 K33 acetylation as a key epigenetic mechanism sustaining anthracycline resistance and suggest that targeting the KAT8-CDK1 axis may provide a therapeutic strategy to overcome refractory breast cancer.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13601616/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149030012","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}
Johanna Stachelscheid, Cäcilia Kaul, Katrin Gerstenberg, J Paul Werthenbach, Fabian Schorn, Joy Steinkamp, Paola Zigrino, Manolis Pasparakis, Lars M Schiffmann, Hamid Kashkar
{"title":"The anti-tumour activity of TNF in melanoma is determined by cFLIP.","authors":"Johanna Stachelscheid, Cäcilia Kaul, Katrin Gerstenberg, J Paul Werthenbach, Fabian Schorn, Joy Steinkamp, Paola Zigrino, Manolis Pasparakis, Lars M Schiffmann, Hamid Kashkar","doi":"10.1038/s41419-026-09154-6","DOIUrl":"10.1038/s41419-026-09154-6","url":null,"abstract":"<p><p>Tumour necrosis factor (TNF) is a pleiotropic cytokine originally identified for its ability to kill cancer cells. However, a paradoxical tumour-promoting role for TNF emerged when early attempts to exploit its anti-tumour activity in cancer therapy produced conflicting outcomes, raising the question of whether TNF should be viewed as a therapeutic agent or a treatment target in cancer. Here, we demonstrate that expression of cFLIP, a catalytically inactive paralogue of caspase-8 (CASP8), determines the susceptibility of melanoma cells to TNF and thereby controls melanoma growth in a syngeneic, immune-competent mouse model of B16F10 cutaneous melanoma. B16F10 melanoma cells lacking cFLIP (cFlip<sup>KO/KO</sup> cells) failed to grow in wild-type mice, whereas in TNF-deficient mice, cFlip<sup>KO/KO</sup> melanoma cells formed palpable tumours and exhibited robust subcutaneous growth. These findings indicate that TNF alone is sufficient to control melanoma growth in the absence of cFLIP. Importantly, the anti-tumour activity of TNF has predominantly been investigated through targeting cellular inhibitors of apoptosis proteins (cIAPs), which promotes RIPK1 activation and TNF-induced cytotoxicity. We show that genomic ablation of cIAPs or RIPK1, in contrast to cFLIP, neither triggered TNF-induced toxicity nor affected melanoma growth in vivo. Collectively, our data underscore the central role of cFLIP in regulating melanoma responses to TNF and suggest that endogenous immune surveillance as well as immunotherapies involving TNF could strongly benefit from cFLIP targeting strategies.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13428747/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148653016","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}
Maj Sofie Ørum-Madsen, Jessica Pihl, Thomas M Clausen, Charlotte Spliid, Anne-Chloé Dhez, Hai-Feng Zhang, Yen-Hsi Chen, Elena Ethel Vidal-Calvo, Tobias Gustavsson, Michael Lizardo, Irina Nelepcu, Joey Lo, Jeffrey D Esko, Htoo Zarni Oo, Alberto Delaidelli, Mette Ørskov Agerbæk, Anne Steinø, Nader Al Nakouzi, Ali Salanti, Poul Sorensen, Mads Daugaard
{"title":"Chondroitin sulfate shapes the unfolded protein response in osteosarcoma to sustain cancer cell survival during ER stress.","authors":"Maj Sofie Ørum-Madsen, Jessica Pihl, Thomas M Clausen, Charlotte Spliid, Anne-Chloé Dhez, Hai-Feng Zhang, Yen-Hsi Chen, Elena Ethel Vidal-Calvo, Tobias Gustavsson, Michael Lizardo, Irina Nelepcu, Joey Lo, Jeffrey D Esko, Htoo Zarni Oo, Alberto Delaidelli, Mette Ørskov Agerbæk, Anne Steinø, Nader Al Nakouzi, Ali Salanti, Poul Sorensen, Mads Daugaard","doi":"10.1038/s41419-026-09151-9","DOIUrl":"10.1038/s41419-026-09151-9","url":null,"abstract":"<p><p>Tumors must adapt to high levels of endoplasmic reticulum (ER) stress to sustain tumor growth and metastases. The chaperone GRP78 (BiP/HSPA5) is a key component of the unfolded protein response (UPR) and essential for ER stress management and adaptive signaling supporting pro-survival UPR activities. Here, we report that oncofetal chondroitin sulfate (CS) glycosaminoglycans are required for ER stress adaptation in osteosarcoma. When osteosarcoma cells encounter ER stress, they upregulate 4-O-sulfated CS at the expense of other glycosaminoglycans leading to a reconfiguration of the glycocalyx in favor of an oncofetal CS subtype. Genetic ablation of the CS synthesis pathway impairs the UPR by preventing osteosarcoma cells from mounting GRP78 expression in response to ER stress. CS deficiency makes osteosarcoma cells hypersensitive to inhibition of GRP78 under both ambient and ER stress conditions, and acute ER stress drives CS-defective osteosarcoma cells into an apoptotic cell death that can be rescued by re-instating CS 4-O-sulfation capacity. This has direct implications for the metastatic progression of osteosarcoma, whereby oncofetal CS protects dissociated osteosarcoma cells from anoikis to allow pulmonary colonization in mice. Our data identify CS glycosaminoglycans as a critical component of the UPR that permits osteosarcoma cells to manage ER stress.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13620160/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149073533","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":"Mycobacterium tuberculosis infects human peripheral hematopoietic multipotent progenitors and promotes their myeloid differentiation in vitro.","authors":"Tonino Alonzi, Daniela Peruzzu, Alessandra Aiello, Giulio Bontempi, Chiara Farroni, Federica Repele, Settimia Sbarra, Valentina Vanini, Ivana Palucci, Michela Sali, Luca Pierelli, Raffaele Strippoli, Giovanni Delogu, Delia Goletti","doi":"10.1038/s41419-026-09122-0","DOIUrl":"10.1038/s41419-026-09122-0","url":null,"abstract":"<p><p>Mycobacterium tuberculosis (Mtb) persists as a global health threat partly by establishing long-term reservoirs in myeloid cells. Although progenitors have been proposed as additional sites of persistence and immune reprogramming, it remains unclear whether circulating human hematopoietic stem/progenitor cells (HSPC) are permissive to Mtb infection. Here, we show that peripheral blood-derived CD34<sup>+</sup> HSPC are permissive to Mtb, in vitro. Confocal microscopy showed Mtb cytoplasmic localization, while colony-forming unit (CFU) quantification demonstrated early intracellular Mtb growth. Flow cytometry revealed preferential Mtb infection of multipotent progenitors (MPP) with progressive enrichment of granulocyte-monocyte progenitors (GMP) and lineage-committed cells, indicating myeloid skewing. Infection drove early IL-8 and TNF-α release, followed by MIP-1α, MIP-1β, and IP-10, demonstrating a dynamic inflammatory response by CD34<sup>+</sup> progenitors. Parallel infection experiments with Mycobacterium bovis BCG revealed that, despite lacking key virulence determinants, BCG infects CD34<sup>+</sup> cells in vitro with a preference for MPP. Unlike Mtb, BCG infection did not promote expansion of more differentiated progenitor subsets, indicating that virulence-dependent mechanisms are required to drive progenitor differentiation and myeloid skewing. These findings identify CD34<sup>+</sup> HSPC as a permissive niche for mycobacterial infection and suggest that Mtb-specific virulence factors contribute to the modulation of progenitor differentiation. Further studies are needed to fully assess the consequences of these events on the systemic immune modulation observed during tuberculosis infection.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642923/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149104537","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":"Non-canonical signaling hubs upon inhibition of MyD88-ERK interaction in cancer.","authors":"Nader Hussein, Najwa Skafi, Thuy Ha Pham, Melina Gautier, Francois Virard, Frédérique Fauvet, Léa Magadoux, Christelle Chassot-Lamblot, Anne-Pierre Morel, Christophe Vanbelle, Bassam Badran, Serge Lebecque, Serge Nicolas Manié, Sylvain Lamure, Toufic Renno, Isabelle Coste","doi":"10.1038/s41419-026-09131-z","DOIUrl":"10.1038/s41419-026-09131-z","url":null,"abstract":"<p><p>The RAS-MAPK pathway is frequently dysregulated in cancer, leading to malignant transformation. We previously identified a direct interaction between MyD88, a central adaptor of inflammatory signaling, and ERK, the terminal kinase of the RAS-MAPK cascade. Pharmacologic disruption of this ERK-MyD88 complex with a small molecule induces immunogenic cell death and antitumor immunity, suggesting a novel therapeutic strategy. Here, we show that ERK-MyD88 inhibition drives cellular signaling from non-canonical hubs. First, ERK-MyD88 disruption activates an integrated stress response that drives caspase-8-dependent apoptosis through a FADD-independent pathway within p62-ubiquitin aggregates. Second, it promotes assembly of MyD88, IRAK1, and IRAK4 into Myddosomes that produce proinflammatory chemokines independently of TLR or IL-1R activation. These findings demonstrate that perturbation of the ERK-MyD88 complex rewires cellular signaling into cell-autonomous hubs that coordinate caspase activation with chemokine secretion, thereby driving a program of immunogenic cancer cell death.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13614936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149058585","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":"Matrix stiffness promotes colorectal cancer progression via Golgi-dependent cholesterol synthesis.","authors":"Min-Yue Yin, Xue Li, Jun-Qi Zhang, Bo-Shen Lin, Chang-Hao Zhang, Yu-Hang Liu, Shu-Tian Zhang, Si-An Xie","doi":"10.1038/s41419-026-09101-5","DOIUrl":"https://doi.org/10.1038/s41419-026-09101-5","url":null,"abstract":"<p><p>Extracellular matrix (ECM) stiffening and metabolic reprogramming are hallmarks of colorectal cancer (CRC) progression; however, the mechanistic link between biomechanical cues and cholesterol metabolism remains poorly defined. Here, we delineate a mechano-metabolic pathway in which matrix stiffness activates the mechanosensitive Ca²⁺ channel Piezo1 to drive structural reorganization of the Golgi apparatus, promoting its close apposition with the endoplasmic reticulum (ER). This organelle remodeling facilitates the proteolytic activation and nuclear translocation of SREBP2, thereby transcriptionally upregulating HMGCR, the rate-limiting enzyme for cholesterol synthesis, and elevating intracellular cholesterol. HMGCR upregulation is functionally essential for stiffness-induced epithelial-mesenchymal transition (EMT) and CRC progression. Mechanistically, HMGCR-mediated cholesterol accumulation promotes phosphorylation of β-catenin at Ser552, which disrupts β-catenin/E-cadherin complexes at adherens junctions, leading to β-catenin nuclear accumulation and EMT execution. Therapeutically, combined pharmacological inhibition of matrix crosslinking and cholesterol synthesis synergistically suppresses tumor growth and invasion while restoring epithelial architecture in vivo. Collectively, these findings reveal that Piezo1-dependent Golgi-ER reorganization triggers SREBP2-driven cholesterol synthesis, ultimately fueling β-catenin-mediated junctional disassembly and metastasis, and highlight the therapeutic promise of co-targeting tumor mechanics and metabolism.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223414","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}
Minghang Yu, Xinhua Liu, Wenxiu Zhang, Xuefeng Huang, Yue Wu, Xinying Wang, Yuanyuan Chen, Ning Ding, Zilong Zhao, Xi Wang, Yang Li
{"title":"Targeting EHMT2 enhances NK cell maturation and antitumor activity.","authors":"Minghang Yu, Xinhua Liu, Wenxiu Zhang, Xuefeng Huang, Yue Wu, Xinying Wang, Yuanyuan Chen, Ning Ding, Zilong Zhao, Xi Wang, Yang Li","doi":"10.1038/s41419-026-09124-y","DOIUrl":"10.1038/s41419-026-09124-y","url":null,"abstract":"<p><p>Natural killer (NK) cells are critical for both innate and adaptive immunity, and their effective regulation holds significant promise for tumor immunotherapy. The terminal maturation of NK cells is closely associated with enhanced effector functions, but the role of epigenetic mechanisms in this process remains incompletely understood. Here, we identify the histone methyltransferase EHMT2 as an epigenetic regulator that restrains NK cell maturation and function. EHMT2 expression is markedly downregulated upon cytokine activation in human NK cells and inversely correlated with effector gene expression across tissues and cancer types. NK cell-specific deletion of Ehmt2 in mice promotes terminal NK cell maturation, augmenting IFN-γ production and cytotoxicity both in vitro and in vivo. Integrated RNA-seq and H3K9me2 CUT&Tag profiling reveal that Ehmt2 loss reduces the repressive histone mark H3K9me2 and derepresses transcriptional programs associated with NK cell differentiation and cytotoxicity. Pharmacological inhibition of EHMT2 recapitulated these effects in both human umbilical cord blood (hUCB)-hematopoietic stem cell (HSC)-derived NK cells and peripheral blood NK cells, promoting terminal maturation and tumor cell killing. These findings define EHMT2-dependent H3K9me2 deposition as a key epigenetic barrier to NK cell effector programming and suggest that targeting EHMT2 may potentiate NK cell-based immunotherapies.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13594311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149015649","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":"Chidamide induces ROS-driven ZAKα-dependent ribotoxic stress in endometrial cancer and enhances radiosensitivity in vitro and in vivo.","authors":"Haocheng Zhang, Zhiling Wang, Xinqin He, Yulong Mu, Xiaonan Fan, Xuan Wei, Hongluan Mao, Shuqi Chi, Zunling Li, Xuehui Pang, Wei Lu, Beihua Kong, Qing Zhang, Yingxin Pang","doi":"10.1038/s41419-026-09125-x","DOIUrl":"https://doi.org/10.1038/s41419-026-09125-x","url":null,"abstract":"<p><p>Chidamide is a selective histone deacetylase inhibitor with antitumor activity in several malignancies, but its mechanism of action in endometrial cancer (EC) remains poorly understood. In this study, we investigated the cytotoxic effects and underlying mechanism of chidamide in EC using cell lines, patient-derived organoids (PDOs), cell-derived xenograft (CDX) models, and patient-derived xenograft (PDX) models. Chidamide markedly inhibited EC cell growth and induced reactive oxygen species (ROS) accumulation, DNA damage, G2/M-phase arrest, and apoptosis. Mechanistically, transcriptomic and functional analyses showed that chidamide disrupted translational homeostasis and activated a ROS-dependent, ZAKα-mediated ribotoxic stress response, leading to p38 and JNK activation. Scavenging ROS with N-acetylcysteine (NAC) attenuated ZAKα-MAPK signaling, and partially rescued chidamide-induced cell cycle arrest and apoptosis. Similarly, pharmacological ZAK inhibition or ZAKα silencing weakened stress signaling and diminished the cytotoxic effects of chidamide, supporting the central role of the ROS-ZAKα-MAPK axis. Chidamide also activated the GCN2-eIF2α-ATF4 integrated stress response, and ISRIB further enhanced stress signaling and apoptosis, suggesting an adaptive buffering role of this pathway. In addition to its activity in vitro, chidamide showed broad antitumor efficacy in PDO, CDX, and PDX models. Chidamide also enhanced tumor radiosensitivity in vivo, supporting its potential utility in combination with radiotherapy. Together, these findings identify ROS-driven, ZAKα-dependent ribotoxic stress signaling as a key mechanism underlying chidamide-induced cytotoxicity in EC and provide a mechanistic rationale for the further development of chidamide-based strategies in this disease.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"17 1","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149223430","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}
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