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However, there are currently no specific and effective treatments available. Inhibiting gasdermin D (GSDMD)\u2010mediated pyroptosis has shown promise in mitigating sepsis\u2010induced myocardial dysfunction. The GSDMD inhibitor Y2 (GI\u2010Y2) has been demonstrated to directly bind to GSDMD. Nonetheless, it remains uncertain whether GI\u2010Y2 offers a cardioprotective effect in the context of sepsis\u2010induced myocardial dysfunction.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>A mouse model of sepsis was created using lipopolysaccharide (LPS), caecal ligation and puncture. Following treatment with GI\u2010Y2 or macrophage membrane\u2010encapsulated GI\u2010Y2 nanoparticles (GI\u2010Y2@MM\u2010NPs), myocardial dysfunction and pyroptosis levels in heart tissues were assessed. Transcriptome sequencing revealed the molecular mechanism of GI\u2010Y2 in treating septic cardiomyopathy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      We observed that GI\u2010Y2 alleviated myocardial dysfunction and attenuated cardiac inflammation in mice induced by LPS, caecal ligation and puncture. GI\u2010Y2 reduced macrophage pyroptosis and attenuated macrophage\u2010mediated cardiomyocyte injury induced by LPS\/nigericin. Concurrently, we confirmed the protective effect of GI\u2010Y2 against LPS\u2010induced cardiac dysfunction was abolished in the absence of GSDMD. Additionally, GI\u2010Y2 attenuated the mitochondrial damage induced by LPS by inhibiting GSDMD in the mitochondria. Furthermore, we developed GI\u2010Y2@MM\u2010NPs to enhance the targeting capability of GI\u2010Y2 towards macrophages in heart tissues and demonstrated its protective effect\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>These findings indicate that GI\u2010Y2 alleviates septic myocardial injury and dysfunction by specifically targeting GSDMD, thereby inhibiting GSDMD\u2010mediated pyroptosis and mitochondrial damage. Both GI\u2010Y2 and GI\u2010Y2@MM\u2010NPs may serve as promising therapeutic options for addressing septic myocardial dysfunction.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.70040","type":"journal-article","created":{"date-parts":[[2025,4,1]],"date-time":"2025-04-01T22:34:11Z","timestamp":1743546851000},"page":"3503-3521","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["GI\u2010Y2, a novel gasdermin D inhibitor, attenuates sepsis\u2010induced myocardial dysfunction by inhibiting gasdermin D\u2010mediated pyroptosis in macrophages"],"prefix":"10.1111","volume":"182","author":[{"given":"Yiling","family":"Mei","sequence":"first","affiliation":[{"name":"The Key Laboratory of Emergency and Disaster Medicine of Wenzhou, Department of Emergency The First Affiliated Hospital of Wenzhou Medical University  Wenzhou Zhejiang China"},{"name":"Department of Cardiology and The Key Laboratory of 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