Yufei Han

Acute myocardial infarction (MI) is a leading cause of mortality worldwide. 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‐A3) as a previously unrecognized cardioprotective factor that plays a central regulatory role in ischemic injury. SR‐A3 was significantly downregulated in myocardial tissues from MI/RI patients. Global or cardiomyocyte‐specific deletion of SR‐A3 exacerbated MI/RI‐induced cardiac damage, whereas AAV9‐mediated overexpression alleviated myocardial injury and improved cardiac function. Notably, SR‐A3 expression in cardiomyocytes underwent the most dramatic reduction upon I/R stress, underscoring its critical role in the injured myocardium. Mechanistically, SR‐A3 interacts with ubiquitin‐specific peptidase 18 (USP18) to suppress interferon‐stimulated gene 15 (ISG15)‐dependent 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‐A3/USP18/ISG15/STING regulatory pathway governing innate immune activation in MI/RI and position SR‐A3 as a promising therapeutic target for ischemic heart disease.