<p>Myocardial ischemia‒reperfusion (I/R) injury is the crucial cause of poor prognosis after revascularization in patients with myocardial infarction (MI) due to the lack of specific therapeutic drugs. Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is related to the pathogenesis and progression of various cardiovascular diseases. However, the specific role of PCSK9 in I/R-induced cardiac injury remains to be further investigated. In this study, wild-type (WT) C57BL/6J mice were administered evolocumab (a monoclonal antibody of PCSK9) before I/R surgery. Cardiac damage and function were assessed by echocardiography and TTC/Evans Blue staining. Inflammation, oxidative stress, mitochondrial dysfunction, and cuproptosis were evaluated by histopathology and qPCR. The interaction between proteins was confirmed by protein docking and co-immunoprecipitation. Our data revealed that PCSK9 level was increased in I/R-induced mouse serum and hearts and in serum of MI patients. Furthermore, evolocumab significantly improved cardiac injury and dysfunction, inflammation, oxidative stress, and cuproptosis. Mechanistically, evolocumab obstructs the direct interaction of PCSK9 and LIAS, and subsequently inhibits cardiomyocyte cuproptosis. In conclusion, inhibition of PCSK9 alleviates I/R-induced cardiac remodeling and dysfunction by targeting LIAS-mediated cuproptosis, which may be a novel therapeutic strategy for patients with ischemic cardiomyopathy.</p>