AbstractAimsRecent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation. Whether the PDK/PDH axis plays a role in vascular inflammation and atherosclerotic cardiovascular disease remains unclear.Methods and resultsGene profiling of human atherosclerotic plaques revealed a strong correlation betweenPDK1andPDK4transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, thePDK1andPDK4expression correlated with a more vulnerable plaque phenotype, andPDK1expression was found to predict future major adverse cardiovascular events. Using the small-molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation inApoe−/− mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque.ConclusionsWe have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans and particularly that thePDK1isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features inApoe−/− mice. These results point toward a promising treatment to combat atherosclerosis.