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Although reperfusion restores coronary blood flow, it paradoxically induces secondary injury that limits therapeutic benefits, and effective interventions for myocardial ischemia\/reperfusion injury (MI\/RI) remain lacking. Here, we identify scavenger receptor class A member 3 (SR\u2010A3) as a previously unrecognized cardioprotective factor that plays a central regulatory role in ischemic injury. SR\u2010A3 was significantly downregulated in myocardial tissues from MI\/RI patients. Global or cardiomyocyte\u2010specific deletion of SR\u2010A3 exacerbated MI\/RI\u2010induced cardiac damage, whereas AAV9\u2010mediated overexpression alleviated myocardial injury and improved cardiac function. Notably, SR\u2010A3 expression in cardiomyocytes underwent the most dramatic reduction upon I\/R stress, underscoring its critical role in the injured myocardium. Mechanistically, SR\u2010A3 interacts with ubiquitin\u2010specific peptidase 18 (USP18) to suppress interferon\u2010stimulated gene 15 (ISG15)\u2010dependent ISGylation, thereby negatively regulating activation of the STING signaling pathway and its downstream innate immune inflammatory cascades. Treatment with Selonsertib, an ASK1 inhibitor that increased USP18 abundance in our MI\/RI model, recapitulated the cardioprotective effects, highlighting the translational potential of targeting this signaling axis. Collectively, our findings uncover a novel SR\u2010A3\/USP18\/ISG15\/STING regulatory pathway governing innate immune activation in MI\/RI and position SR\u2010A3 as a promising therapeutic target for ischemic heart disease.<\/jats:p>","DOI":"10.1002\/advs.77196","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:07:32Z","timestamp":1786968452000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["SR\u2010A3 Promotes USP18\u2010Mediated deISGylation of STING to Protect Against Myocardial Ischemia\u2010Reperfusion Injury"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-0307-6186","authenticated-orcid":false,"given":"Yufei","family":"Han","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Sciences State Key Laboratory of Vascular Homeostasis and Remodeling School of Basic Medical Sciences Peking University  Beijing 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