{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T06:02:41Z","timestamp":1780293761457,"version":"3.54.0"},"reference-count":174,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T00:00:00Z","timestamp":1780272000000},"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>Pyroptosis is a lytic form of regulated cell death driven by inflammasome activation and gasdermin-mediated membrane rupture, characterized by robust inflammatory amplification. High-mobility group box 1 (HMGB1), a multifunctional nuclear protein and damage-associated molecular pattern, has emerged as a central regulator within pyroptosis-associated pathologies. Acting both as a downstream alarmin released during pyroptotic cell death and as an upstream licensing factor for inflammasome activation and innate immune signaling, HMGB1 establishes a context-dependent feedforward loop that shapes tissue injury and immune responses. In infectious and inflammatory disorders, excessive HMGB1 release exacerbates immune dysregulation and organ damage, whereas in selected tumor settings, pyroptosis-associated HMGB1 contributes to immunogenic cell death and antitumor immunity. This review systematically summarizes the molecular mechanisms underlying HMGB1-regulated pyroptosis, including canonical and noncanonical inflammasome pathways, gasdermin execution, and crosstalk with other regulated cell death programs. We further integrate evidence implicating the pyroptosis\u2013HMGB1 axis across systemic diseases involving the nervous, respiratory, digestive, circulatory, urinary, locomotor, endocrine, reproductive, and immune systems. Finally, we discuss emerging therapeutic strategies targeting this axis, highlighting opportunities and challenges for disease-specific and precision interventions.<\/jats:p>","DOI":"10.3389\/fcell.2026.1814812","type":"journal-article","created":{"date-parts":[[2026,6,1]],"date-time":"2026-06-01T05:27:54Z","timestamp":1780291674000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Involvement of the pyroptosis\u2013HMGB1 axis in systemic diseases"],"prefix":"10.3389","volume":"14","author":[{"given":"Ting","family":"Wang","sequence":"first","affiliation":[{"name":"Department of General Surgery, Lequn Branch, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Le","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, The Affiliated Hospital of Changchun University of Traditional Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Du","sequence":"additional","affiliation":[{"name":"Department of Endocrinology and Spleen-Stomach Diseases, The Third Affiliated Hospital of Changchun University of Chinese Medicine","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiuli","family":"Miao","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, Lequn Branch, The First Hospital of Jilin University","place":["Changchun, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.jphs.2021.08.005","article-title":"Granisetron attenuates liver injury and inflammation in a rat model of cecal ligation and puncture-induced sepsis","volume":"147","author":"Aboyoussef","year":"2021","journal-title":"J. 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