• Succinate accumulation is elevated in CHD patients and DEBM-treated HUVECs, correlating with increased inflammatory cytokines IL-6 and IL-18.
• Succinate accumulation induces pyroptosis and mitochondrial damage in HUVECs, evidenced by upregulation of pyroptosis-related proteins and impaired mitochondrial structure/function.
• ATP5F1D is identified as a key downstream target of succinate accumulation; its downregulation promotes pyroptosis and mitochondrial injury, while restoration mitigates these effects.
• The study provides a novel mechanism linking metabolic dysregulation (succinate) to endothelial pyroptosis via ATP5F1D, offering potential therapeutic targets for atherosclerosis.