Abstract

The formation of macrophage-derived foam cells is a critical factor in the development of atherosclerotic lesions. However, the mechanisms through which the cuproptosis pathway contributes to macrophage foam cell formation remain unclear. This study aimed to investigate the role and mechanisms of the cuproptosis inducer Elesclomol in atherosclerosis. Macrophages were exposed to ox-LDL to establish a foam cell model. Subsequently, CCK8, oil red O staining, and Western blot were used to investigate foam cell formation and the cuproptosis pathway in macrophages. Furthermore, proteomics analysis was employed to explore the molecular mechanisms underlying the effects of Elesclomol. The results demonstrated that Elesclomol promoted foam cell formation by increasing lipid accumulation in ox-LDL-treated macrophages, which was attributed to the inhibition of cholesterol efflux mediated by ATP-binding cassette transporters A1 and G1 (ABCA1 and ABCG1). Additionally, Elesclomol enhanced the cuproptosis pathway in macrophages, leading to increased intracellular ROS accumulation and consequent cell death. Mechanistically, the cytotoxic effects of Elesclomol were mediated through activation of the mitogen-activated protein kinase (MAPK) pathway and upregulation of metallothionein 2A (MT2A). Collectively, these findings underscore the critical role of cuproptosis in the pathogenesis of atherosclerosis and suggest that targeting this pathway may represent a promising therapeutic strategy for the disease.