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Emerging evidence indicates that GSDMs exert diverse functions in health and various disease contexts, which can be either dependent on or independent of pyroptosis, including facilitating mucus secretion, regulating bone resorption, and modulating mitochondrial metabolism. This review provides a comprehensive overview of the GSDM family, detailing the molecular mechanisms of activation, regulation, pore formation, cell rupture and membrane repair. We explored the extensive crosstalk between GSDMs and other cell death modalities, including apoptosis, necroptosis, NETosis, and PANoptosis. Furthermore, we systematically discuss GSDMs\u2019 \u2018double-edged sword\u2019 roles in diverse pathologies, ranging from host defense in infectious diseases and chronic inflammation in autoimmune disorders to their complex, context-dependent function in cancer progression and immunity. Finally, we evaluate emerging therapeutic strategies, encompassing small-molecule inhibitors such as disulfiram (DSF), necrosulfonamide (NSA) and dimethyl fumarate (DMF), as well as novel material-based delivery systems. Collectively, these advances underscore the therapeutic potential of targeting GSDMs for precise clinical intervention to treat both inflammatory and non-inflammatory diseases, as well as to enhance cancer immunotherapy.<\/jats:p>","DOI":"10.1038\/s41392-026-02867-2","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T23:02:03Z","timestamp":1790895723000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The gasdermin family: from pyroptosis mechanisms to therapeutic targets"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-0628-1346","authenticated-orcid":false,"given":"Weilv","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyang","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zexu","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhuang","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fushan","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,2]]},"reference":[{"key":"2867_CR1","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1038\/s41392-024-01801-8","volume":"9","author":"C Zhu","year":"2024","unstructured":"Zhu, C. et al. 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