SUMMARY In atherosclerotic cardiovascular disease (ASCVD), chronic inflammation is a major risk factor that remains unaddressed by currently approved therapies. Existing therapies aimed at curbing ASCVD target lipid metabolic pathways, and many patients continue to be at high risk of cardiovascular disease including myocardial infarction and stroke. Although inhibition of the pro-inflammatory cytokine interleukin (IL)-1β was shown in the CANTOS trial to reduce adverse cardiovascular events, the concomitant increased risk of fatal infections hindered its therapeutic viability. Therefore, narrowing the gap between metabolism and immune cell function to discern the processes governing inflammation resolution in ASCVD—and why they fail with disease progression—is a major challenge in the field. To that end, we have identified itaconate, a TCA cycle-derived metabolite produced by the enzyme cis-aconitate decarboxylase (ACOD1/IRG1), as a driver of inflammation resolution in atherosclerosis. Itaconate is induced during microbial infection, and harbors anti-microbial and immunomodulatory functions, including inhibition of the NLRP3-inflammasome, IL-1β secretion and reactive oxygen production. These inflammatory pathways contribute centrally to atherogenesis, yet the regulation of IRG1 and impact of itaconate on plaque immune responses has yet to be studied. In this proposal, we aim to (i) determine the metabolic and immune processes by which the IRG1-itaconate axis curbs inflammatory responses in atherosclerosis and (ii) investigate the effects of itaconate and its derivatives on atherosclerosis-associated inflammatory responses in vitro, and iii) test whether the cell-permeable itaconate derivative 4-octyl-itaconate can reduce plaque burden and instability in mice. Our studies will use novel mouse models to track itaconate abundance in vivo and innovative 3D human vascular explants to investigate therapeutic modulation of the IRG1-itaconate axis in ASCVD. Collectively, these investigations will identify novel mechanisms of metabolic control of local and systemic inflammation during atherosclerosis and provide a foundation for the design of targeted immunometabolic therapies for ASCVD.