Cell Death Discovery最新文献

{"title":"Lipid droplets in neurodegenerative diseases: pathological drivers and therapeutic vulnerabilities.","authors":"Ourania Papapanagiotou, Kian Cotton, Christopher Edwards, David Michod, Lucy Crompton, Tim Craig, Maria Victoria Niklison-Chirou","doi":"10.1038/s41420-026-03096-w","DOIUrl":"https://doi.org/10.1038/s41420-026-03096-w","url":null,"abstract":"<p><p>Lipid droplets (LDs) are dynamic intracellular organelles traditionally associated with energy storage, which have become increasingly recognised for their versatile roles in cellular metabolism and signalling. In the brain, LDs have emerged as critical regulators in neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), and Hereditary Spastic Paraplegia (HSP). LDs contribute to neurodegeneration by influencing lipid metabolism, oxidative stress, and inflammatory responses. For instance, in AD, dysregulated lipid metabolism and impaired Apolipoprotein E 4 (ApoE4) function lead to LD accumulation associated with neuroinflammation and amyloid plaque formation. In PD, interactions between LDs and α-synuclein suggest a potential link between lipid dysregulation and neurotoxicity. Mutations in LD-associated proteins, such as spastin and DDH2 in HSP, highlight the importance of proper LD regulation for neuronal health. While LD accumulation can be protective by mitigating lipotoxicity, prolonged dysregulation can exacerbate NDD pathology. Targeting LD metabolism, through enhancing lipophagy or modulating LD-associated proteins, represents a promising therapeutic avenue. This review highlights the dual roles of LDs in the brain, acting both neuroprotectively and neurotoxically, and the therapeutic potential of targeting LD dynamics for NDD treatment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644265","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":"ARHGAP21 enhances metastasis in hepatocellular carcinoma by inhibiting ubiquitination of filamin A.","authors":"Huijun Yao, Ziping Xie, Xingyu Tao, Xingyi Zhong, Xiaoxiao Wang, Kaiwen Xi, Zhiqin Zhu, Yangfeng Zhang, Feiye Liu, Junhao Lin, Fengsheng Chen","doi":"10.1038/s41420-026-03103-0","DOIUrl":"https://doi.org/10.1038/s41420-026-03103-0","url":null,"abstract":"<p><p>Rho GTPase-activating protein 21 (ARHGAP21) plays a role in the occurrence and development of certain cancers, but its function in hepatocellular carcinoma (HCC) remains unclear. In this study, elevated ARHGAP21 expression was observed in both HCC cell lines and tissues and correlated with poor patient prognosis. Knockdown of ARHGAP21 suppressed HCC cell migration and invasion in vitro by regulating the actin cytoskeleton, while overexpression of ARHGAP21 had the opposite effect. In vivo, knockdown of ARHGAP21 inhibited HCC tumorigenesis and metastasis. Mechanistically, we demonstrated that ARHGAP21 directly binds to FLNA, and the PDZ domain of ARHGAP21 functions as a potential mediator of its binding to the 1-1200 aa fragment of FLNA. ARHGAP21 also directly binds to and recruits HSP90α to stabilize FLNA by inhibiting its ubiquitination and degradation. Overexpression of FLNA reversed the cytoskeleton remodeling-related suppression of tumor metastasis in ARHGAP21-knockdown HCC cells. These results revealed that ARHGAP21 promotes cytoskeleton remodeling and stimulates HCC metastasis by inhibiting FLNA ubiquitination and degradation via HSP90α recruitment. Our results position ARHGAP21 as both a potential prognostic marker and a promising therapeutic target in HCC.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644228","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":"Glycosylation-driven necroptosis in retinal degeneration: dual rescue by AAV8 gene therapy and RIPK1 inhibition.","authors":"Jia-Ying Chien, Peng Yeong Woon, Hsien-Yang Tsai, Mei-Ling Peng, Shi-Huang Lee, Siu-Fung Chau, Yu-Chen Chen, Wai-Man Cheang, Ching-Yen Tsai, Shun-Ping Huang","doi":"10.1038/s41420-026-03098-8","DOIUrl":"https://doi.org/10.1038/s41420-026-03098-8","url":null,"abstract":"<p><p>Glycosylation defects are increasingly implicated across neurodegenerative diseases, yet the mechanism by which perturbed O-mannosylation drives neuronal death-and how to reverse it-remains unclear. Here we show that a disease-associated POMGnT1 L120R mutation produces widespread retinal neurodegeneration by coupling metabolic collapse to necroptosis. In mice harboring the human POMGnT1 L120R allele and in POMGnT1-knockout human RPE cells, hypoglycosylation of key substrates (α-dystroglycan and ENO1) coincides with strengthened SAG-ENO1 interaction, reduced glycolytic capacity, ATP shortfall, Golgi fragmentation, tight-junction failure, and robust activation of the RIPK1/RIPK3/MLKL cascade; notably, degeneration proceeds with minimal apoptotic signatures. Two orthogonal interventions-AAV8-mediated POMGnT1 gene augmentation and pharmacologic RIPK1 inhibition (RIPA-56)-each suppress necroptotic signaling, restore barrier integrity, and rescue visual function in vivo. These data define a glycosylation-metabolism-necroptosis axis that generalizes beyond a single gene or tissue and motivate a mutation-independent therapeutic blueprint: repair the upstream glycosylation deficit and/or block the downstream necroptotic execution pathway. Our findings position O-mannosylation homeostasis as a tractable control point for neuroprotection and nominate combined gene-augmentation and kinase-inhibition strategies for glycosylation-linked neurodegeneration.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644207","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":"Low-dose TNF-α drives malignant progression and lipid metabolism in glioblastoma through the TRAF2-FASN axis.","authors":"Maorong Cai, Yang Liu, Xinyu Mao, Yiping Wu, Shoujia Sun, Jing Zhou, Tao Huang, Jiantong Jiao","doi":"10.1038/s41420-026-03087-x","DOIUrl":"https://doi.org/10.1038/s41420-026-03087-x","url":null,"abstract":"<p><p>Lipid metabolism plays a critical role in the progression of cancers, including glioblastoma (GBM). Tumor necrosis factor-α (TNF-α) exhibits a dual role in the tumor microenvironment: at high concentrations, it induces cell death and exerts anti-tumor effects, while at low doses, it demonstrates pro-tumorigenic activity. This study investigates the regulatory effects of low-dose TNF-α on the malignant behavior and lipid metabolism of GBM. The results show that low-dose TNF-α (10 ng/mL) significantly promotes GBM cell malignant phenotypes and lipid droplet accumulation via the Tumor Necrosis Factor Receptor (TNFR) signaling pathway, a process dependent on its downstream adaptor protein, Tumor necrosis factor receptor-associated factor 2 (TRAF2). Mechanistically, TRAF2 interacts with Fatty acid synthase (FASN) through its TRAF domain and, serving as an E3 ubiquitin ligase, leverages its RING domain to mediate K63-linked polyubiquitination of FASN. This enhances FASN protein stability, promotes lipid synthesis, and ultimately drives tumor progression. Furthermore, through virtual screening, the small-molecule compound Jionoside B1 was identified to target the RING domain of TRAF2, effectively inhibiting K63-linked ubiquitination of FASN and disrupting the TRAF2-FASN interaction and protein accumulation. In both in vitro and in vivo experiments, Jionoside B1 significantly suppressed lipid synthesis and attenuated tumor growth. This study systematically elucidates the mechanism by which low-dose TNF-α regulates lipid metabolism and promotes GBM malignant progression via the TRAF2-FASN axis, providing not only new insights into the \"double-edged sword\" role of TNF-α in the tumor microenvironment but also a potential novel therapeutic strategy for targeting this pathway in GBM treatment.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147644248","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":"Proteasome dysfunction underlies HERC2-linked neurodevelopmental disorder with Angelman-like clinical features.","authors":"Joan Sala-Gaston, Laura Costa-Sastre, Manel Garcia-Diez, Tania López-Hernández, Juanma Ramírez, Nerea Osinalde, Jose Antonio Valer, Claudia Arnedo-Pac, Bernat Crosas, Emma L Baple, Andrew H Crosby, Ugo Mayor, Francesc Ventura, Jose Luis Rosa","doi":"10.1038/s41420-026-03095-x","DOIUrl":"https://doi.org/10.1038/s41420-026-03095-x","url":null,"abstract":"<p><p>Biallelic hypomorphic variants in the E3 ubiquitin ligase HERC2 cause a neurodevelopmental disorder clinically resembling Angelman syndrome, characterized by global developmental delay, intellectual disability, autism spectrum features, and movement abnormalities. Defining the target substrates of HERC2 is essential for understanding its biological role and the mechanisms underlying its pathological variants. To this end, we performed a quantitative proteomic analysis using biotinylated ubiquitin to identify HERC2 targets and assess their regulation in cells expressing HERC2 with or without ubiquitin‑ligase activity. This approach revealed extensive sets of subunits from major multimeric complexes, including the proteasome, the tRNA-biosynthesis machinery, microtubule‑associated assemblies, vesicle‑coat complexes, centrosomes, and the Ski and GATOR2 complexes, as substrates of HERC2-dependent ubiquitylation. Among these, the proteasome emerged as the most prominently affected complex. We identified up to eleven proteins required for assembly of the 19S regulatory particle whose ubiquitylation depends on HERC2. Mechanistically, we show that HERC2 recognizes unassembled subunits via chaperone-mediated interactions and targets them for proteasomal degradation. Loss of this mechanism in HERC2‑deficient cells alters proteasomal activity. It is noteworthy that fibroblasts derived from patients carrying the common pathogenic variant c.1781 C > T (p.Pro594Leu) exhibit impaired processing of 19S subunits and an aberrant increase in proteasome activity. Our findings establish a link between HERC2-related neurodevelopmental disorder and impaired proteasome activity, elucidate the molecular mechanisms through which HERC2 regulates proteostasis and how its disruption contributes to human pathology, and underscore potential therapeutic strategies for affected individuals.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147637998","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":"Leveraging drug-specific genes to identify sensitizers for resistant cancer cell lines.","authors":"G Pepe, E Valentini, R Appierdo, C Pontecorvi, L Parca, G Ausiello, S Galardi, M Helmer-Citterich, P F Gherardini","doi":"10.1038/s41420-026-03033-x","DOIUrl":"https://doi.org/10.1038/s41420-026-03033-x","url":null,"abstract":"<p><p>Therapeutic resistance remains a major obstacle in oncology, often arising from transcriptional reprogramming that enables cancer cells to escape drug-induced cytotoxicity. We aimed to develop a computational-experimental strategy to identify compounds capable of reversing resistance phenotypes. We integrated previously defined Drug-Specific Genes (DSGs), expression markers of drug sensitivity or resistance, with perturbational profiles from the Connectivity Map (CMap). Candidate compounds were prioritized based on their predicted ability to shift DSG expression toward a sensitized state. The top-ranked compound was validated in resistant HeLa and NCI-H1299 cell lines using BMS-345541 and Vorinostat as primary agents. Cell viability, apoptosis, and cell cycle progression were assessed. Chaetocin consistently emerged as a leading sensitizer in silico. Experimental validation confirmed that chaetocin enhanced the activity of BMS-345541 in HeLa cells and Vorinostat in NCI-H1299 cells. Combination treatments reduced cell viability, induced apoptosis, and promoted G2/M cell cycle arrest compared with primary drugs alone. DSG-guided transcriptional reversal offers a rational framework for overcoming therapeutic resistance. Our findings demonstrate that chaetocin can restore drug sensitivity in resistant cancer models, supporting its potential as a resistance-modulating agent in combination therapies. Given its epigenetic activity, chaetocin aligns with the emerging role of epigenetic modulators as promising partners in oncological co-treatments.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632559","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":"FGFR1 suppresses ovarian cancer progression by modulating SIRT3-dependent lactylation and metabolic reprogramming.","authors":"Fan Jiang, Huaju Huang, Zhe Dong, Lu Zhang, Shiti Zhang, Mengnan Long, Xue Fan, Nan Li, Hao Ai","doi":"10.1038/s41420-026-03054-6","DOIUrl":"https://doi.org/10.1038/s41420-026-03054-6","url":null,"abstract":"<p><p>Ovarian cancer (OC) is an aggressive gynecological malignancy with poor prognosis, largely due to late-stage diagnosis and high metastatic potential. However, the functional role and regulatory mechanisms of fibroblast growth factor receptor 1 (FGFR1) in OC remain incompletely understood. In this study, we investigated the expression pattern and biological function of FGFR1 in OC and explored its underlying molecular mechanisms. FGFR1 expression was analyzed using TCGA, GTEx, and tissue microarray datasets, and its prognostic significance was evaluated by Kaplan-Meier survival analysis. Functional assays were performed in OVCAR-3 and SK-OV-3 cells following FGFR1 knockdown or overexpression to assess cell proliferation, migration, invasion, and metabolic activity, including extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Lactate production and histone lactylation were measured by biochemical assays and Western blotting. Protein interaction between FGFR1 and SIRT3 was examined by co-immunoprecipitation and immunofluorescence, and rescue experiments were conducted to determine SIRT3 dependency. In vivo subcutaneous xenograft models were used to evaluate the role of FGFR1 in tumor growth. We found that FGFR1 expression was significantly reduced in OC tissues and that low FGFR1 levels were associated with unfavorable clinical outcomes. Functionally, FGFR1 silencing promoted OC cell proliferation, migration, invasion, and metabolic activity, whereas FGFR1 overexpression exerted inhibitory effects. Mechanistically, FGFR1 interacted with SIRT3 and stabilized its protein expression. Importantly, SIRT3 knockdown abrogated the FGFR1-mediated reductions in lactate production, glycolytic enzyme expression, ATP levels, and histone lactylation, indicating that FGFR1 regulates metabolic reprogramming through a SIRT3-dependent mechanism. Consistently, FGFR1 knockdown promoted the formation of larger and more invasive tumors in vivo. Collectively, these findings demonstrate that FGFR1 functions as a context-dependent tumor suppressor in OC by modulating SIRT3-mediated metabolic reprogramming and histone lactylation, suggesting that targeting the FGFR1-SIRT3 axis may represent a potential therapeutic strategy for ovarian cancer.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632547","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":"Programmed cell death in cancer: targeting necroptosis to kill tumor cell.","authors":"Jiahao Liang, Chenchen Tan, Xia Li, Jialong Fan, Bin Liu","doi":"10.1038/s41420-026-03002-4","DOIUrl":"https://doi.org/10.1038/s41420-026-03002-4","url":null,"abstract":"<p><p>Necroptosis is a precisely regulated form of programmed cell death (PCD) that exhibits necrotic morphology while being orchestrated receptor-interacting protein kinase 1 (RIPK1), receptor-interacting protein kinase 3 (RIPK3), and mixed lineage kinase domain-like pseudokinase (MLKL). In tumor biology, necroptosis plays a context-dependent dual role: it can suppress tumor progression by inducing immunogenic cell death (ICD) and activating anti-tumor immune responses; yet it may also promote tumor progression and immunosuppression by triggering inflammatory responses. Emerging evidence indicates that small molecule compounds, natural products, and nanomedicine technologies can effectively induce necroptosis in tumor cells, providing opportunities to overcome traditional chemotherapy resistance and enhance anti-tumor immunity. However, clinical translation faces numerous challenges, including frequent downregulation of key necroptotic proteins, the lack of robust predictive biomarkers, and potential tumor-promoting effects. This review offers an integrative perspective linking necroptosis molecular mechanisms, dual functional outcomes, and therapeutic strategies, highlighting both opportunities and risks. By providing mechanistic insights and a framework for rational design of necroptosis-based interventions, this work aims to guide future research toward effective and safe anticancer therapies.Schematic illustration of the mechanisms, dual roles in tumor therapy, and inducers of necroptosis.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147627249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: The cytotoxicity of gomesin peptides is mediated by the glycosphingolipid pathway and lipid-cholesterol interactions.","authors":"Isabel Fernandez-Carrasco, Javier Moral-Sanz, Sergey Kurdyukov, Èlia Obis, Lissy Maike Hartmann, Silvia Carina Magalhães Novais, Matthew A Waller, Naomi McKinnon, Felicity Chung, Francisco Javier Salazar Castejón, Daniel P Rainho, Zoltan Dekan, Thomas Kremsmayr, Bernhard Jandl, Kristina Eleršič Filipič, Reinald Pamplona, Mariona Jové, Manuel A Fernandez-Rojo, Gregor Anderluh, Markus Muttenthaler, Paul F A Alewood, Jan Procházka, G Gregory Neely, Evelyne Deplazes, Maria P Ikonomopoulou","doi":"10.1038/s41420-026-03009-x","DOIUrl":"10.1038/s41420-026-03009-x","url":null,"abstract":"","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":"12 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13046979/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608158","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":"Excessive pyroptosis mediates the exacerbation of pneumonia caused by low-lethality influenza virus and secondary MRSA co-infection.","authors":"Zi-Chen Tian, Yang Liu, Yi-Jun Niu, Xin Ai, Su-Ya Lao, Wei-Ming Xu, Xiao-Tong Lin, Cheng-Jie Xia, Zhi-Xuan Cai, Hai-Yan Zhu, Xun-Long Shi","doi":"10.1038/s41420-026-03031-z","DOIUrl":"https://doi.org/10.1038/s41420-026-03031-z","url":null,"abstract":"<p><p>Co-infection with influenza A virus (IAV) and methicillin-resistant Staphylococcus aureus (MRSA) often causes severe pneumonia clinically; however, the role of innate immunity in this setting remains poorly understood. In our study, we established a murine co-infection model using low-lethality IAV and MRSA. Compared with single IAV or MRSA infection, co-infection with relatively low-lethality IAV and MRSA resulted in more severe pneumonia. Transcriptomic analysis indicated marked upregulation of genes involved in the pyroptotic signaling pathway. Consistently, flow cytometry and immunofluorescence analyses revealed caspase-1 activation and colocalization of gasdermin D (GSDMD) with macrophages in the lung. The RAW264.7 macrophage cell line was used for in vitro validation. Co-infection significantly enhanced the cleavage of caspase-1 and GSDMD in RAW264.7 cells. Furthermore, disulfiram, a pyroptosis inhibitor, was incorporated into the antiviral and antibacterial combination treatment. Although combined oseltamivir and linezolid treatment failed to fully alleviate lung injury, the inclusion of disulfiram, a GSDMD pore formation inhibitor, significantly ameliorated pneumonia symptoms and reduced inflammatory responses. Collectively, our findings highlight that macrophage pyroptosis contributes to the exacerbation of pneumonia induced by IAV and secondary MRSA co-infection. Inhibition of GSDMD-mediated pyroptosis may represent a viable therapeutic approach to alleviate disease severity and improve outcomes in lethal co-infection.</p>","PeriodicalId":9735,"journal":{"name":"Cell Death Discovery","volume":" ","pages":""},"PeriodicalIF":7.0,"publicationDate":"2026-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147608146","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}