Cell Death Discovery最新文献

{"title":"Mitochondrial IκBα fuels cancer progression through metabolic rewiring, endothelial activation, and thrombotic spread.","authors":"Menga Alessio, Jessica Petiti, Roberta Basile, Pietro Poggio, Davide Acquarone, Alfonso Scalera, Lidia Avalle, Francesca Orso, Alessandra Bertoni, Paolo Ettore Porporato, Chiara Riganti, Lukasz Truszkowski, Isaia Barbieri, Mara Brancaccio, Carla Riera Domingo, Federica Cappellesso, Chiara Donno, Maiara Caroline Colombera, Massimiliano Mazzone, Giovanna Carrà, Alessandro Morotti","doi":"10.1038/s41420-026-03022-0","DOIUrl":"https://doi.org/10.1038/s41420-026-03022-0","url":null,"abstract":"<p><p>Mitochondria play a central role in metastatic spread and cancer progression, with the IκBα/NF-κB signaling axis acting as a key regulator of both processes. We suggest that a stable fraction of IκBα localizes to mitochondria, where it escapes proteasomal degradation and acquires oncogenic functions independent of its canonical role in NF-κB inhibition. Using engineered A549 lung cancer cells with enforced mitochondrial localization of IκBα (IκBα-MTS), we show that the IκBα mitochondrial pool promotes increased cell proliferation, enhanced migration, and resistance to chemotherapy-induced apoptosis, along with a metabolic reprogramming characterized by elevated glycolysis and lactate secretion. These changes activated endothelial cells (ECs) and triggered cancer-associated thrombosis (CAT). This prothrombotic state, marked by elevated vWF a potent trigger for platelet adhesion and activation, contributed to an environment favorable for metastatic dissemination. Our findings reveal mitochondrial IκBα as a key mediator in mitochondrial stress, endothelial activation, and thrombo-inflammatory mechanisms that drive lung cancer progression.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147520174","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":"MEKK3 bridges gut-brain communication and cerebral cavernous malformation pathogenesis.","authors":"Peng Cheng, Hongkuan Han, Ying Huang, Yang Shen, Xuan Jiang, Xiaoxiong Song, Cheng Qian, Lei Chen, Yang Zhao","doi":"10.1038/s41420-026-03062-6","DOIUrl":"10.1038/s41420-026-03062-6","url":null,"abstract":"<p><p>Cerebral cavernous malformation (CCM) is a condition affecting the brain vasculature, characterized by endothelial dysfunction and abnormal vascular structure. In recent years, the gut-brain axis has emerged as a significant regulatory factor influencing cerebrovascular health. The gut microbiota, through its metabolites, immune modulation, and signaling interactions with the brain, plays a critical role in the pathogenesis of CCM. Research indicates that dysbiosis can trigger systemic inflammatory responses via pathways such as lipopolysaccharide (LPS) -TLR4, short-chain fatty acids (SCFAs), and trimethylamine N-oxide (TMAO), ultimately affecting cerebrovascular function and the integrity of the blood-brain barrier. Additionally, the gut-brain axis may influence the proliferation, migration, and apoptosis of endothelial cells, potentially promoting or inhibiting the development of CCM. Although the exact mechanisms linking the gut-brain axis and CCM remain unclear, existing studies suggest a potential key role in the pathological progression of CCM. This review explores the mechanisms by which the gut-brain axis contributes to CCM and proposes that targeting relevant pathways within the gut-brain axis may offer new therapeutic strategies for CCM.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144326/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147527155","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":"Inflammatory macrophage-derived plasminogen activator inhibitor-1 exacerbates inflammation through efferocytosis inhibition.","authors":"Abd Aziz Ibrahim, Hiromi Miura, Tomoya Terada, Masaki Kawarada, Nobuo Watanabe, Hiroyuki Hosokawa, Masato Ohtsuka, Toshio Miyata, Takashi Yahata","doi":"10.1038/s41420-026-03076-0","DOIUrl":"10.1038/s41420-026-03076-0","url":null,"abstract":"<p><p>Plasminogen activator inhibitor-1 (PAI-1) is significantly upregulated during inflammatory responses, and elevated PAI-1 levels are associated with poor prognosis in various diseases. However, the precise mechanism through which PAI-1 exacerbates inflammation remains unclear. In the present study, we have investigated the role of PAI-1 in inflammation using a mouse model of skeletal muscle injury. We found that CCR2⁺Ly6C⁺ inflammatory macrophages infiltrated the injured tissues and produced substantial amounts of PAI-1. Notably, PAI-1 deficiency specifically in these macrophages resulted in attenuated inflammation and accelerated tissue repair despite the continued presence of PAI-1 in body fluids, indicating a local macrophage-driven effect. Low-density lipoprotein receptor-related protein-1 (LRP-1), expressed on macrophages, is a common receptor for both PAI-1 and calreticulin (CRT). CRT is exposed on the surface of dying cells and functions as an \"eat me\" signal recognized by macrophages via LRP-1. We found that PAI-1 binds to LRP-1 with higher affinity than that to CRT, thereby competitively inhibiting CRT recognition and suppressing efferocytosis, the process by which macrophages clear dead cells, ultimately leading to prolonged inflammation. Importantly, administration of a PAI-1 inhibitor, TM5614, restored efferocytosis and significantly improved tissue regeneration. These findings therefore reveal that PAI-1 produced by infiltrating inflammatory macrophages contributes to sustained inflammation by blocking efferocytosis, and that PAI-1 is a promising therapeutic target for the treatment of inflammatory diseases. Dead cells expose an \"eat-me\" signal molecule CRT, which is recognized by the LRP-1 receptor on macrophages, leading to their phagocytosis through a process known as efferocytosis. However, PAI-1, secreted by infiltrating CCR2⁺Ly6c⁺ macrophages, impairs tissue regeneration after injury by inhibiting efferocytosis through competitive binding to LRP-1, thereby prolonging inflammation.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147520166","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":"Therapeutic potential of cAMP-mediated lysosomal pH modulation in ATP6V1B2-related neuropathology.","authors":"Lu Zheng, Weihao Zhao, Guang Yang, Shiwei Qiu, Yahong Li, Lin Gao, Gege Wei, Ying Ma, Jiangping Xie, Xue Gao, Linyan Chen, Xiaoge Li, Rongfeng Lin, Wei Xiong, Yongyi Yuan, Pu Dai","doi":"10.1038/s41420-026-03056-4","DOIUrl":"10.1038/s41420-026-03056-4","url":null,"abstract":"<p><p>Pathogenic variants in ATP6V1B2, which encodes a critical subunit of vacuolar-type H+-ATPases (V-ATPases), disrupt lysosomal acidification via haploinsufficiency and clinically manifest as intellectual disability and seizure disorders. Despite significant morbidity, mechanism-based therapies remain an unmet need. Through integrated clinical analysis of a Chinese cohort and systematic literature review, we delineated genotype-phenotype correlations in ATP6V1B2-related syndromes. Isogenic HEK293T models (ATP6V1B2^R506X/+ and ATP6V1B2^R506X/R506X) were generated using CRISPR/Cas9 for dynamic lysosomal pH monitoring via ratiometric RpH-LAMP1-3×flag imaging to evaluate pathophysiological mechanisms. Parallel investigations in Atp6v1b2^R506X/R506X mice incorporated continuous video-EEG monitoring, behavioral assessments, western blot analyses, and transmission electron microscopy to evaluate therapeutic responses. Drug concentrations in plasma and brain homogenates were quantified by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Clinical analysis revealed central nervous system manifestations (epilepsy, intellectual disability, developmental delay) as primary morbidity determinants. Cellular studies demonstrated significant increase of lysosomal pH in mutant cells compared to wild-type control. Remarkably, treatment with the cAMP analog CPT-cAMP restored lysosomal acidification in a concentration-dependent manner. In vivo studies confirmed spontaneous seizure activity in mutant mice and CPT-cAMP's penetration of the BBB was confirmed by LC-MS/MS. Intraperitoneal CPT-cAMP administration (20 mg/kg) exerted triple therapeutic effects: (1) significant reduction in seizure frequency, (2) improved cognitive performance in behavioral paradigms, and (3) restoration of autophagic flux through resolution of autophagosome accumulation. These findings establish proof-of-concept for cAMP-mediated lysosomal pH modulation as a viable therapeutic strategy. Our results position CPT-cAMP as a promising candidate for addressing both neurological and cognitive manifestations in ATP6V1B2-related disorders.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13150000/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147527107","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":"IOA-244, a novel p110δ PI3K inhibitor, blocks breast tumour progression on either mono- or combined-therapy.","authors":"Evangelia Goulielmaki, Anna Tsapara, Lydia Xenou, Zoe Johnson, Karolina Niewola-Staszkowska, Maria Tzardi, Eelco de Bree, Evangelia A Papakonstanti","doi":"10.1038/s41420-026-03073-3","DOIUrl":"https://doi.org/10.1038/s41420-026-03073-3","url":null,"abstract":"<p><p>The clinical approval of p110δ PI3K inhibitors raised hopes in treating aggressive tumours expressing high levels of non-mutated p110δ, however, the severe adverse effects that those inhibitors caused became a barrier to their clinical application. IOA-244 is the first-in-class, highly selective and non-ATP competitive p110δ PI3K inhibitor showing high selectivity and low toxicity in several preclinical models. Here we show that IOA-244, as a single agent treatment, blocks the progression of early phase breast tumours by attacking the survival of cancer cells and the polarisation of TAMs to a pro-tumourigenic phenotype leading to suppression of TAMs-expressed ATX. In established tumours, IOA-244 alone was insufficient to control the high levels of both M2-like macrophages and ATX, and while it reduced tumour progression, it did not completely block it. Full tumour control, however, was achieved when IOA-244 used in a combinatorial regimen with the PF-8380 ATX inhibitor. In agreement with the mouse model, the amount of CD163+/CD204+macrophages and ATX were much higher in grade III human breast carcinomas compared to grade I. Our work provides the first in vivo preclinical evidence showing that IOA-244 is a potential highly effective drug for breast cancer treatment and depending on the phase of the tumour can be used either as a single agent or as a combinatorial regimen.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147527099","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":"NRIP1 co-activates nuclear translocated FOXO3 to upregulate TFAM expression and promote radioresistance in non-small cell lung cancer.","authors":"Ying Zha, Hui Huang, Yulian Liu, Mengzhi Wan, Qinqin Yao, Hongtao Chen, Jianping Xiong, Min Zhong","doi":"10.1038/s41420-026-03028-8","DOIUrl":"10.1038/s41420-026-03028-8","url":null,"abstract":"<p><p>Radioresistance remains a major obstacle in the treatment of non-small cell lung cancer (NSCLC). This study investigated the coordinated regulation of TFAM, FOXO3, and NRIP1 in NSCLC radioresistance. Radioresistant cell lines (A549-RR and H157-RR) were established to examine the effects of silencing these factors on cellular responses to radiation. In vivo, the impact of FOXO3 knockdown on tumor growth under irradiation was evaluated using A549-RR xenografts. Results show that TFAM expression was elevated in radioresistant cells, and its knockdown significantly restored radiosensitivity. ChIP-qPCR demonstrated direct FOXO3 binding to TFAM regulatory regions, establishing FOXO3 as an upstream transcriptional activator of TFAM. Silencing FOXO3 reduced TFAM expression and enhanced radiosensitivity, whereas LOM612, a FOXO nuclear relocator, promoted FOXO3 nuclear accumulation, upregulated TFAM, and reduced radiosensitivity. NRIP1 deficiency constrains FOXO3-dependent regulation of TFAM. Restoring NRIP1 selectively enhanced TFAM without affecting FOXO3 abundance, indicating its role as a coactivator. Co-immunoprecipitation confirmed FOXO3/NRIP1 interaction in NSCLC cells, with stronger interactions observed in radioresistant cells. Accordingly, NRIP1 silencing decreased TFAM levels and increased radiosensitivity. In vivo, FOXO3 knockdown markedly suppressed A549-RR tumor growth and improved radiotherapy response. Collectively, these findings indicate that nuclear accumulation of FOXO3 drives NSCLC radioresistance by transcriptionally upregulating TFAM, with NRIP1 enhancing this regulatory activity. Targeting FOXO3 may represent a promising strategy to enhance radiosensitivity in NSCLC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147520211","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":"Targeting glioblastoma mitochondrial metabolism with S-Gboxin induces cytotoxicity under conditions of the tumor microenvironment.","authors":"Jan-Béla Weinem, Hans Urban, Benedikt Sauer, Tanja Buhlmann, Ann-Christin Hau, Stefan Liebner, Tillmann Rusch, Dmitry Namgaladze, Leander F Harwart, Jan-Hendrik Schröder, Maeve de Souza, Joachim P Steinbach, Stefan Legewie, Anna-Luisa Luger, Michael W Ronellenfitsch","doi":"10.1038/s41420-026-03072-4","DOIUrl":"10.1038/s41420-026-03072-4","url":null,"abstract":"<p><p>Glioblastoma (GB) is the most common primary malignant brain tumor in adults. Gboxin, a novel compound that targets oxidative phosphorylation via complex V inhibition, has shown promise in preclinical models of GB. We examined the efficacy of the pharmacokinetically optimized S-Gboxin under conditions replicating the GB microenvironment, including nutrient deprivation and hypoxia. We assessed cytotoxicity and growth-inhibitory effects of S-Gboxin in human GB cell lines, primary GB cultures, as well as immortalized and primary human astrocytes under different nutrient and oxygen deprivation scenarios. Oxygen consumption, cell migration, activation of the integrated stress response (ISR) as well as the relevance of the AMP-activated protein kinase (AMPK) were evaluated as variables under S-Gboxin treatment. S-Gboxin demonstrated cytotoxicity at low micromolar concentrations, with cell death enhanced under nutrient deprivation and hypoxia. S-Gboxin reduced cellular oxygen consumption and uncoupled mitochondria. Cytotoxicity was increased when mitochondrial fuels were the primary energy source. Additionally, S-Gboxin treatment resulted in elevated lactate production and glucose consumption. While the ISR marker ATF4 was induced by S-Gboxin in a dose-dependent manner, ISR inhibition with ISRIB did not affect its cytotoxicity. Conversely, S-Gboxin treatment combined with AMPK inhibition resulted in enhanced tumor cell death. Collectively, these findings demonstrate that S-Gboxin selectively targets cancer-specific metabolic vulnerabilities in GB cells. The synergistic action with AMPK inhibition suggests that this pathway contributes to maintain energy homeostasis in the presence of the drug. Therefore, S-Gboxin is a promising compound for GB therapy, especially in a combinatory approach with AMPK inhibition or other metabolic targeted therapies.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13066480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147527085","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":"c-Myc transactivates CFL1 to induce senescence-like phenotype and potentiate the bystander effects for the migration and proliferation in lung cancer cells.","authors":"Yen-Ting Chou, Jyh-Der Leu, Wan-Yu Yang, Chien-Hsiu Li, Min-Ying Lin, Chia-Wei Kao, Yu-Chan Chang, Michael Hsiao, Yi-Jang Lee","doi":"10.1038/s41420-026-03065-3","DOIUrl":"10.1038/s41420-026-03065-3","url":null,"abstract":"<p><p>Oncogene-induced senescence (OIS) is regarded a tumor suppressive mechanism in normal cells. Accumulated evidences, however, demonstrate that OIS would play a role in cancer promotion through the secretion of senescence associated secretory phenotypes (SASP). The underlying mechanisms remain to be addressed. In this study, we found that c-Myc oncogene could induce senescence in human diploid lung fibroblasts and non-small cell lung cancer cells (NSCLC) without concomitant emergence of apoptosis. c-Myc-induced senescence (cMIS) caused morphological enlargement, increased F-actin and nuclear G-actin that generally detected in senescent cells. These events were found to be associated with increased expression of cofilin-1, an actin-binding protein required for actin dynamics. Transfection of c-Myc could induce cofilin-1, but transfection of truncated Myc-Nick mutant and inhibition of c-Myc reduced cofilin-1 expression. Additionally, knockdown of cofilin-1 could suppress cMIS. The chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR) assay showed that the endogenous c-Myc mainly bound to two out of three predicted E-boxes located in middle and proximity to the transcription initiation site of the CFL1 promoter. Interestingly, ectopic expression of c-Myc bound to all E-boxes, especially the distal one. Furthermore, the conditioned medium (CM) collected from cells with cMIS could enhance the proliferation and migration of other NSCLC cells, whereas that obtained from cofilin-1 silencing cells with forced expression of c-Myc diminished these capacities. The c-Myc transactivated cofilin-1 could also be triggered by H₂O₂ through the middle E-box. Surprisingly, a physical interaction between c-Myc and cofilin-1 was detected, and H₂O₂ increased this effect. Clinically, high expression of both c-Myc and CFL1 genes correlated to worse survival rates among NSCLC patients, especially those with the adenocarcinoma subtype. Taken together, the c-Myc-cofilin-1 regulatory axis would explain the mechanism of OIS promoted cancer progression, and it may be a potent target for design of treatments.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147520169","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":"RRx-001 inhibits G6PD to deplete NADPH and trigger disulfidptosis coupled with DAMP-mediated immunogenic cell death in hepatocellular carcinoma.","authors":"Hailian Huang, Yongfei He, Jingxuan Chen, Yuan Liao, Shutian Mo, Wei Qin, Meifeng Chen, Tianyi Liang, Guohong Yan, Shuxin Wei, Qichong Xie, Xiaoling Luo, Chuangye Han","doi":"10.1038/s41420-026-03032-y","DOIUrl":"10.1038/s41420-026-03032-y","url":null,"abstract":"&lt;p&gt;&lt;p&gt;Disulfidptosis is a recently identified form of programmed cell death driven by NADPH metabolic imbalance and disulfide stress, but its therapeutic relevance in hepatocellular carcinoma (HCC) remains poorly understood. RRx-001, a clinical-stage small-molecule agent known for its epigenetic modulatory and radiosensitizing effects, has yet to be explored for its potential to induce disulfidptosis and immunogenic cell death (ICD). This study investigated the mechanism by which RRx-001 triggers disulfidptosis in HCC through NADPH metabolic dysregulation and evaluated its capacity to elicit ICD and antitumor immunity. Using Huh-7 and Hepa1-6 HCC cell lines and a murine subcutaneous xenograft model, we assessed drug sensitivity (CCK-8), apoptosis (flow cytometry), metabolic parameters (NADPH, GSH/GSSG, ROS), and ultrastructural changes (transmission electron microscopy). Protein expression was analyzed by immunofluorescence and Western blotting. In vivo antitumor efficacy was evaluated, and immune microenvironment dynamics were characterized via transcriptomic sequencing, immunohistochemistry, and flow cytometry, with all animal experiments randomized and blinded. RRx-001 markedly reduced NADPH levels by downregulating G6PD, leading to redox imbalance (decreased GSH/GSSG ratio, elevated ROS) and F-actin cytoskeletal contraction-hallmarks of disulfidptosis. This process was partially reversed by the disulfide reductant TCEP, confirming disulfidptosis dependency; quantitative F-actin fluorescence intensity showed significant contraction in RRx-001-treated cells that was mitigated by TCEP co-treatment (p &lt; 0.01). Additionally, RRx-001 promoted the release of damage-associated molecular patterns (DAMPs), including CRT, HMGB1, and HSP70/90, activating ICD, as confirmed by ELISA of extracellular HSP70/90. In vivo, RRx-001 significantly suppressed tumor growth (p &lt; 0.001), reduced tumor weight, enhanced infiltration of CD4+ and CD8+T cells, increased M1 macrophage polarization, and downregulated PD-L1 expression. Transcriptomic analysis implicated enhanced antitumor immunity via T-cell receptor signaling and T-helper cell differentiation pathways. These findings demonstrate that RRx-001 triggers disulfidptosis in HCC by targeting the G6PD-NADPH axis while concurrently inducing ICD, achieving dual metabolic and immunomodulatory effects. This mechanistic insight provides a scientific foundation for developing novel disulfidptosis-based HCC therapies with high translational potential and suggests that future studies should explore the synergistic efficacy of RRx-001 with immune checkpoint inhibitors. This study uncovers the therapeutic mechanism of RRx-001 in hepatocellular carcinoma (HCC): by inhibiting G6PD, it reduces NADPH levels, leading to redox imbalance and F-actin contraction, thereby inducing disulfidptosis-a process that can be partially reversed by TCEP. Meanwhile, RRx-001 promotes the release of DAMPs, activating immunogenic cell death (ICD). ","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13144330/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147520127","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":"A novel PAAoptosis-inducing ERRα-targeting compound for combating hematopoietic and solid cancers.","authors":"Wonhyoung Seo, Yerim Heo, Khang Vuong Tran, So-Young Kim, Eun Jung Bae, Bokeum Jung, Sang-Hee Lee, Taylor Roh, Sang Min Jeon, Kyung Tae Kim, Eun-Jin Park, Soo In Kim, Jeong Suk Koh, Ik-Chan Song, Hyun Kyu Song, Jung-Joon Min, Jin Hee Ahn, Eun-Kyeong Jo","doi":"10.1038/s41420-026-03010-4","DOIUrl":"10.1038/s41420-026-03010-4","url":null,"abstract":"<p><p>Estrogen-related receptor-α (ERRα; NR3B1) is an orphan nuclear receptor that drives the progression of several cancers. To develop novel ERRα-targeting therapeutics, we designed and evaluated the function of a new compound, PAMT-001, which interacts with ERRα and effectively suppresses tumorigenesis. We demonstrated a significant interaction between ERRα and PAMT-001 using protein-small molecule binding assays and luciferase assays. Although PAMT-001 exhibited lower activity compared to the established ERRα inverse agonist XCT-790, it showed stronger anticancer effects against both hematological and solid tumors. Mechanistically, PAMT-001 promoted combined cell death mechanisms in tumors. It disrupted mitochondrial respiratory function and structure, leading to excessive production of reactive oxygen species and endoplasmic reticulum stress, ultimately resulting in apoptotic cell death. Additionally, PAMT-001 induced excessive autophagy, contributing to cancer cell death, as well as gasdermin E-mediated pyroptosis in acute myeloid leukemia and colon cancer cells. Furthermore, PAMT-001 demonstrated potential for use in precision medicine, particularly for patients with chemotherapy-resistant and NPM1-mutated acute myeloid leukemia. PAMT-001 is a potent ERRα-targeting anticancer agent capable of inducing anticancer effects through pyroptosis, autophagic cell death, and apoptosis-a newly termed mechanism referred to as \"PAAoptosis.\" It holds significant potential for the treatment of both hematological and solid cancers.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13139410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147509895","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}