{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T22:20:23Z","timestamp":1785450023735,"version":"3.56.0"},"reference-count":88,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T00:00:00Z","timestamp":1765411200000},"content-version":"vor","delay-in-days":10,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CNS Neurosci Ther"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Myocardial ischemia\u2013reperfusion injury (MIRI) represents an inevitable risk event for acute myocardial infarction. We explored the mechanism of hypoxia\u2010induced high\u2010mobility group box\u00a01 (HMGB1) promoting MIRI by modulating the NLRP3 inflammasome\/Caspase\u20101 pathway\u2010mediated pyroptosis via the Nrf2\/HO\u20101 pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In vitro cultured mouse cardiomyocytes were exposed to hypoxia\/reoxygenation (H\/R) to establish an MIRI cell model, then treated with short hairpin\u2010HMGB1, a NLRP3 agonist (Nigericin), and a Nrf2 inhibitor (ML385). Cell viability and injury were assessed via MTT and LDH assays. HMGB1 (nuclear\/cytoplasm), Nrf2 (nuclear\/cytoplasm), HO\u20101, NLRP3, ASC, cleaved Caspase\u20101, and GSDMD\u2010N protein levels, and IL\u20101\u03b2 and IL\u201018 levels in cell supernatants were determined by western blot and ELISA. HMGB1 and Nrf2 distribution were analyzed by immunofluorescence, with their interaction verified by co\u2010immunoprecipitation. An MIRI mouse model was developed and treated with HMGB1 Box A for in\u00a0vivo verification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>H\/R induction declined the nuclear HMGB1 protein level and cell viability, and intensified the cytoplasmic HMGB1 protein level, cell damage, and pyroptosis\u2010related protein and inflammatory cytokine levels, which were averted by HMGB1 knockdown. NLRP3 activation partially reversed HMGB1 knockdown's effect on improving cardiomyocyte pyroptosis. Hypoxia\u2010induced HMGB1 inhibited Nrf2\/HO\u20101 activation by interacting with Nrf2. Nrf2\/HO\u20101 suppression partly counteracted HMGB1 knockdown's suppressive effects on NLRP3 inflammasome activation and pyroptosis. HMGB1 suppressed the Nrf2\/HO\u20101 axis to enhance NLRP3 inflammasome\/Caspase\u20101 pathway\u2010mediated pyroptosis, thereby exacerbating MIRI in\u00a0vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Hypoxia induces HMGB1's nucleus\u2010to\u2010cytoplasm translocation, which binds to Nrf2 to repress Nrf2 nuclear translocation to suppress Nrf2\/HO\u20101 activation to promote NLRP3 inflammasome\/Caspase\u20101\u2010mediated pyroptosis, thereby exacerbating MIRI.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/cns.70661","type":"journal-article","created":{"date-parts":[[2025,12,11]],"date-time":"2025-12-11T13:49:53Z","timestamp":1765460993000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Mechanism of Hypoxia\u2010Induced\n                    <scp>HMGB1<\/scp>\n                    Regulating\n                    <scp>NLRP3<\/scp>\n                    Inflammasome\/Caspase\u20101 Pathway\u2010Mediated Pyroptosis in Myocardial Ischemia Reperfusion Injury Through the Nrf2\/\n                    <scp>HO<\/scp>\n                    \u20101 Pathway"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-9503-2093","authenticated-orcid":false,"given":"Fuzhen","family":"Zheng","sequence":"first","affiliation":[{"name":"Shengli Clinical Medical College of Fujian Medical University  Fuzhou Fujian China"},{"name":"Department of Cardiovascular Surgery Fuzhou University Affiliated Provincial Hospital  Fuzhou Fujian China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Licheng","family":"Yan","sequence":"additional","affiliation":[{"name":"Shengli Clinical Medical College of Fujian Medical University  Fuzhou Fujian China"},{"name":"Department of Cardiovascular Surgery Fuzhou University Affiliated Provincial Hospital  Fuzhou 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