{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:49:30Z","timestamp":1793296170657,"version":"4.5.0"},"reference-count":132,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Sepsis is a life-threatening organ dysfunction that leads to 11 million annual global deaths. It is characterized by severe immune dysregulation, with gasdermin D (GSDMD)-driven pyroptosis recognized as a key pathogenic mechanism. After exposure to pathogen-associated molecular patterns (PAMPs)\/damage-associated molecular patterns (DAMPs), GSDMD, activated via the canonical (caspase-1) and non-canonical (caspase-4\/5\/11) pathways, forms plasma membrane pores, induces cell lysis, and triggers multi-organ injury. Specifically, GSDMD pores trigger lung inflammation via alveolar macrophage pyroptosis, induce hepatic high mobility group box 1 protein (HMGB1) release, perpetuate bacteremia, cause renal microthrombosis, and disrupt the blood-brain barrier. GSDMD drives both the hyperinflammatory phase (via cytokine storm, NETosis) and the immunosuppressive phase (via lymphocyte apoptosis, T-cell exhaustion), thereby defining hyperinflammatory (GSDMD-NT &amp;gt;120 ng\/mL) and immunosuppressive (intestinal barrier failure) endotypes. Promising therapeutic agents include disulfiram (blocking Cys191 oligomerization), anti-GSDMD mAb26.5 (decreasing mortality to 30%), and the combination of imipenem and disulfiram. Clinical translation faces challenges in terms of biomarker validation, organ-specific delivery, and phase-adapted intervention. Future research directions include AI-based drug design, exosome-mediated CRISPR knockout, clinical trials on drug repurposing, and single-cell omics-integrated stratified immunotherapy.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1801896","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T04:21:36Z","timestamp":1776745296000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Gasdermin D-driven pyroptosis in sepsis: mechanisms, therapeutic strategies, and clinical translation"],"prefix":"10.3389","volume":"17","author":[{"given":"Zixia","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, The Second Hospital and Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The Second Hospital and Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yuan","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The Second Hospital and Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqiang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The Second Hospital and Clinical Medical School, Lanzhou University","place":["Lanzhou, Gansu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock 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