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By coupling cell death to innate immune activation, pyroptosis occupies a unique position at the interface of host defense and tissue pathology. Recent advances have demonstrated that pyroptosis is activated through multiple molecular routes, including canonical and noncanonical inflammasome pathways, Caspase\u20103\/8\u2013gasdermin axes, and granzyme\u2010dependent mechanisms. Importantly, pyroptosis does not operate in isolation but engages in extensive crosstalk with other programmed cell death modalities, such as apoptosis, necroptosis, ferroptosis, NETosis, and the integrative process of PANoptosis, sharing key regulators including caspases, inflammasomes, and gasdermins. Despite rapid progress, a unified framework integrating pyroptosis\u2010specific mechanisms with interaction networks, temporal dynamics, and disease relevance is still lacking. In this review, we systematically dissect the molecular pathways governing pyroptosis, emphasize its functional interplay with other cell death programs, and discuss emerging concepts such as cell\u2010type specificity and sublytic versus lytic outcomes. We further examine the contribution of pyroptosis to cancer, infectious, autoimmune, metabolic, and cardiovascular diseases, and critically evaluate therapeutic strategies aimed at either inhibiting excessive pyroptosis or exploiting it for immunogenic cell death. Collectively, this review offers a perspective\u2010enhancing, mechanistic, and translational significance.<\/jats:p>","DOI":"10.1002\/mco2.70844","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T08:00:20Z","timestamp":1783411220000},"source":"Crossref","is-referenced-by-count":2,"title":["The Multifaceted Role of Pyroptosis: Molecular Mechanisms, Crosstalk with Other Cell Death Pathways, and Therapeutic Implications"],"prefix":"10.1002","volume":"7","author":[{"given":"Diego Liviu","family":"Boaru","sequence":"first","affiliation":[{"name":"Department of Medicine and Medical Specialties Faculty of Medicine and Health Sciences Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD) University of Alcal\u00e1  Alcal\u00e1 de Henares Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia","family":"De Castro\u2010Martinez","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialties Faculty of Medicine and Health Sciences Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD) University of Alcal\u00e1  Alcal\u00e1 de Henares Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cielo","family":"Garcia\u2010Montero","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialties Faculty of Medicine and Health Sciences Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD) University of Alcal\u00e1  Alcal\u00e1 de Henares Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar","family":"Fraile\u2010Martinez","sequence":"additional","affiliation":[{"name":"Department of Medicine and Medical Specialties Faculty of Medicine and Health Sciences Network Biomedical Research Center for Liver and Digestive Diseases (CIBEREHD) University of Alcal\u00e1  Alcal\u00e1 de Henares Spain"},{"name":"Ram\u00f3n y Cajal Institute of Sanitary Research (IRYCIS)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Majd N. 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