{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T12:34:34Z","timestamp":1770813274358,"version":"3.50.1"},"reference-count":96,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"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. Cell Dev. Biol."],"abstract":"<jats:p>Heat stroke and sepsis are a pair of acute critical illnesses with distinct underlying causes yet remarkably similar final outcomes. Heat stroke arises from high-temperature environments, disrupting the body\u2019s heat production and dissipation balance; sepsis stems from infection, triggering an uncontrollable inflammatory storm. Both conditions carry extremely high mortality rates and poor prognoses, causing near-total damage to organs and tissues throughout the body. Existing clinical treatments cannot fully reverse the damage inflicted by these diseases. Recent studies have identified necroptosis mediated by the Z-DNA-binding protein 1 (ZBP1) - receptor interaction protein kinase 3 (RIPK3) - mixed lineage kinase-like protein (MLKL) signaling pathway and pyroptosis mediated by the cysteine-aspartic acid proteases-11 (caspase-11) - Gasdermin D (GSDMD) pathway as key mechanisms in heat stroke and sepsis, respectively. Therefore, this review synthesizes recent research findings to analyze the convergent cellular programmed death mechanisms of these two distinct conditions from the perspectives of molecular sensors (a probe for disease triggers) and cell death effectors: ZBP1 senses heat stress, while caspase-11 responds to LPS signaling, initiating downstream membrane-breaching mechanisms executed by MLKL and GSDMD. These processes converge and jointly drive organ damage. The shared pathological outcomes of these distinct diseases suggest that developing broad-spectrum inhibitors targeting their common downstream cell death pathways may represent a novel therapeutic direction.<\/jats:p>","DOI":"10.3389\/fcell.2026.1778368","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T06:52:03Z","timestamp":1770792723000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Cell death mechanisms in heat stroke and sepsis: ZBP1 and caspase-11 as molecular sensors driving the MLKL\/GSDMD death execution axis"],"prefix":"10.3389","volume":"14","author":[{"given":"Xiao-Jie","family":"Qin","sequence":"first","affiliation":[{"name":"School of Pharmacy, Guangxi University of Chinese Medicine","place":["Nanning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cai-Shen","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Faculty of Chinese Medicine Science Guangxi University of Chinese Medicine","place":["Nanning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi-Qi","family":"Li","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangxi University of Chinese Medicine","place":["Nanning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Biao-Chao","family":"Zhong","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangxi University of Chinese Medicine","place":["Nanning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qian-Tong","family":"Wei","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangxi University of Chinese Medicine","place":["Nanning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chun-Hui","family":"Zeng","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangxi University of Chinese Medicine","place":["Nanning, China"]},{"name":"Guangxi Engineering Research Center for High-Value Utilization of Guangxi-Produced Authentic medicinal Herbs, Guangxi University of Chinese Medicine","place":["Nanning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ke","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Pharmacy, Guangxi University of Chinese Medicine","place":["Nanning, China"]},{"name":"University Engineering Research Center of Characteristic Traditional Chinese Medicine and Ethnomedicine, Guangxi University of Chinese Medicine","place":["Nanning, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1097\/00003246-200107000-00002","article-title":"Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care","volume":"29","author":"Angus","year":"2001","journal-title":"Crit. 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