Macrophages play a protective role in atherosclerosis, whereas homocysteine (Hcy) is recognized as an independent risk factor for atherosclerosis. Defects in macrophage autophagy contribute to the formation of atherosclerotic plaques, and dysregulated energy metabolism is closely linked to the process of autophagy. However, the regulation of macrophage autophagy by pyruvate dehydrogenase (PDH), a key component of the PDH complex involved in energy and metabolic homeostasis, remains poorly understood in the context of atherosclerosis induced by Hcy. In our study, proteomic profiling identifies 748 upregulated proteins and 760 downregulated proteins in Hcy-treated macrophages. KEGG pathway analysis reveals significant enrichment of differentially expressed proteins in metabolism-related pathways, including those related to the biosynthesis of amino acids, carbon metabolism, and glycolysis/gluconeogenesis. Additionally, we explore the role of PDH in mediating Hcy-induced atherosclerosis in ApoE