{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T04:53:32Z","timestamp":1775710412749,"version":"3.50.1"},"reference-count":39,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100016808","name":"Natural Science Foundation of Xiamen Municipality","doi-asserted-by":"crossref","award":["3502Z20227262"],"award-info":[{"award-number":["3502Z20227262"]}],"id":[{"id":"10.13039\/100016808","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Regulated cardiomyocyte death is a central contributor to myocardial infarction (MI)-associated injury. Mixed lineage kinase domain-like protein (MLKL), a key effector of necroptosis, has been implicated in cardiovascular disease; however, its role in MI remains incompletely defined. MLKL expression was evaluated in hypoxia-treated cardiomyocytes, infarcted murine hearts, and human cardiac tissue. MLKL function was investigated using siRNA-mediated knockdown in neonatal mouse cardiomyocytes and genetic deletion in mice subjected to left anterior descending (LAD) coronary artery ligation. Apoptosis- and pyroptosis-related signaling were assessed by immunoblotting and immunostaining. RIP3 expression and regulation were examined at both protein and mRNA levels, and the RIP3 inhibitor GSK\u2019872 was used to assess pathway dependence. MLKL expression was increased in hypoxic cardiomyocytes, infarcted mouse hearts, and human failing cardiac tissue. Unexpectedly, MLKL deficiency was associated with aggravated myocardial injury, impaired cardiac function, and increased fibrosis following MI. Mechanistically, MLKL deficiency was associated with increased RIP3 protein abundance without a corresponding increase in RIP3 mRNA, consistent with post-transcriptional regulation. Further analyses indicated that MLKL deficiency reduced RIP3 ubiquitination and impaired proteasome-mediated degradation, resulting in RIP3 stabilization. Elevated RIP3 levels were accompanied by increased expression of apoptosis- and pyroptosis-related proteins, particularly at early time points after MI. Pharmacological inhibition of RIP3 with GSK\u2019872 was associated with reduced apoptosis- and pyroptosis-related signaling and improved cardiac function. MLKL deficiency is associated with stabilization of RIP3 and enhanced activation of apoptosis- and pyroptosis-related signaling following MI, contributing to aggravated myocardial injury. These findings support a regulatory role for the MLKL\u2013RIP3 axis in cardiomyocyte death and suggest that targeting RIP3 may represent a potential therapeutic strategy in myocardial infarction.<\/jats:p>","DOI":"10.3390\/cimb48040380","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T09:40:31Z","timestamp":1775554831000},"page":"380","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MLKL Deficiency Stabilizes RIP3 and Aggravates Myocardial Injury by Promoting Apoptosis and Pyroptosis"],"prefix":"10.3390","volume":"48","author":[{"given":"Ziguan","family":"Zhang","sequence":"first","affiliation":[{"name":"Xiamen Key Laboratory of Cardiac Electrophysiology, Department of Cardiology, Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuheng","family":"Liu","sequence":"additional","affiliation":[{"name":"Xiamen Key Laboratory of Cardiac Electrophysiology, Department of Cardiology, Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yilei","family":"Liu","sequence":"additional","affiliation":[{"name":"Xiamen Key Laboratory of Cardiac Electrophysiology, Department of Cardiology, Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Changqing","family":"Sun","sequence":"additional","affiliation":[{"name":"Xiamen Key Laboratory of Cardiac Electrophysiology, Department of Cardiology, Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weihua","family":"Li","sequence":"additional","affiliation":[{"name":"Xiamen Key Laboratory of Cardiac Electrophysiology, Department of Cardiology, Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wuyang","family":"Zheng","sequence":"additional","affiliation":[{"name":"Xiamen Key Laboratory of Cardiac Electrophysiology, Department of Cardiology, Xiamen Institute of Cardiovascular Diseases, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361003, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.yjmcc.2022.08.002","article-title":"Glutamine uptake and catabolism is required for myofibroblast formation and persistence","volume":"172","author":"Gibb","year":"2022","journal-title":"J. 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