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Itaconate, a macrophage\u2010derived metabolite, has been implicated in inflammation and metabolic regulation. This study investigates the protective role of itaconate derivatives against IR injury. Using a mice model of IR injury, the impact of 7\u2010day 4\u2010Octyl itaconate (4\u2010OI) administration on cardiac function is assessed. Exogenous administration of 4\u2010OI significantly reduces myocardial damage, enhances angiogenesis, and alleviates myocardial hypoxia injury during reperfusion. RNA sequencing and molecular docking techniques are used to find the target of itaconate, and changes in cardiac function are observed in Immune\u2010Responsive Gene1 (IRG1) global knockout mice. In cell culture studies, 4\u2010OI promotes endothelial cell proliferation and migration, mediated by Mitogen\u2010Activated Protein Kinases (MAPK) signaling pathway activation, particularly through Extracellular Signal\u2010Regulated Kinase (ERK) signaling. Inhibition of ERK blocks these beneficial effects on endothelial cells. Furthermore, itaconate synthesis inhibition worsens myocardial damage, which is mitigated by 4\u2010OI supplementation. The results indicate that 4\u2010OI promotes angiogenesis by activating MAPK signaling via FMS\u2010like tyrosine kinase 1 (Flt1), highlighting its potential as a therapeutic strategy for myocardial IR injury.<\/jats:p>","DOI":"10.1002\/advs.202411554","type":"journal-article","created":{"date-parts":[[2025,1,21]],"date-time":"2025-01-21T13:15:09Z","timestamp":1737465309000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["4\u2010Octyl Itaconate Alleviates Myocardial Ischemia\u2010Reperfusion Injury Through Promoting Angiogenesis via ERK Signaling Activation"],"prefix":"10.1002","volume":"12","author":[{"given":"Jiqin","family":"Yang","sequence":"first","affiliation":[{"name":"Key Laboratory of Cardiovascular and Cerebrovascular Medicine School of Pharmacy Nanjing Medical University  101 Longmian Avenue, Jiangning District Nanjing 211166 P. R. 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