Pyruvate dehydrogenase alleviates macrophage autophagy in Hcy-induced ApoE–/– mice

• Proteomic analysis reveals significant metabolic reprogramming in Hcy-treated macrophages, with 748 upregulated and 760 downregulated proteins enriched in amino acid biosynthesis, carbon metabolism, and glycolysis/gluconeogenesis pathways. • PDH expression and activity are markedly reduced in Hcy-treated macrophages, leading to impaired autophagy and contributing to atherosclerotic plaque formation in ApoE–/– mice. • PDH activation enhances the assembly of the ULK1-FIP200-Atg13 autophagy initiation complex via modulation of the AMPK/mTOR signaling pathway, identifying a novel regulatory mechanism. • These findings suggest that targeting PDH activity could serve as a potential therapeutic strategy for Hcy-induced atherosclerosis.