The IRG1–itaconate axis protects from cholesterol-induced inflammation and atherosclerosis. Atherosclerosis is driven by unresolved lipid-driven inflammation in the vasculature, leading to plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recent studies highlight the immunomodulatory properties of metabolites, including itaconate, which is generated by the enzyme IRG1/ACOD1. This study investigates the therapeutic potential of the IRG1–itaconate axis in human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), it was found that IRG1 is upregulated in human coronary atherosclerotic lesions compared to healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic Irg1 deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine IL-1β. Mechanistically, Irg1 deficiency increases macrophage lipid accumulation and accelerates inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1β release. Conversely, supplementation of the IRG1–itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1β levels in mice. In humans, 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. These findings highlight the therapeutic promise of targeting the IRG1–itaconate pathway for the treatment of atherosclerosis. The study shows that IRG1 is expressed in atherosclerotic plaques and its deficiency increases plaque burden. Conversely, supplementing the IRG1–itaconate axis with 4-OI induces beneficial remodeling of advanced atherosclerotic plaques in mice and reduces CVD-associated inflammation in human immune cell populations. These findings underscore the therapeutic promise of targeting the IRG1–itaconate pathway for the treatment of CVD. The study also shows that IRG1 is expressed in myeloid cells of human and mouse atherosclerotic plaques, yet its expression wanes with disease progression. Loss-of-function studies in mouse models of atherosclerosis demonstrate that global and hematopoietic Irg1 deficiency increase atherosclerotic burden, plaque lipid content, and indices of plaque instability. Mechanistically, Irg1 deficiency increases NET formation, which acts as a priming signal for the NLRP3 inflammasome in macrophages. In turn, Irg1-defThe IRG1–itaconate axis protects from cholesterol-induced inflammation and atherosclerosis. Atherosclerosis is driven by unresolved lipid-driven inflammation in the vasculature, leading to plaque formation. Therapeutic approaches to reverse atherosclerotic inflammation are needed to address the rising global burden of cardiovascular disease (CVD). Recent studies highlight the immunomodulatory properties of metabolites, including itaconate, which is generated by the enzyme IRG1/ACOD1. This study investigates the therapeutic potential of the IRG1–itaconate axis in human atherosclerosis. Using single-cell RNA sequencing (scRNA-seq), it was found that IRG1 is upregulated in human coronary atherosclerotic lesions compared to healthy vasculature, and in mouse models of atherosclerosis, where it is primarily expressed by plaque monocytes, macrophages, and neutrophils. Global or hematopoietic Irg1 deficiency in mice increases atherosclerosis burden, plaque macrophage and lipid content, and expression of the proatherosclerotic cytokine IL-1β. Mechanistically, Irg1 deficiency increases macrophage lipid accumulation and accelerates inflammation via increased neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3-inflammasome in macrophages, resulting in increased IL-1β release. Conversely, supplementation of the IRG1–itaconate axis using 4-octyl itaconate (4-OI) beneficially remodeled advanced plaques and reduced lesional IL-1β levels in mice. In humans, 4-OI attenuates proinflammatory phospho-signaling and mediates anti-inflammatory rewiring of macrophage populations. These findings highlight the therapeutic promise of targeting the IRG1–itaconate pathway for the treatment of atherosclerosis. The study shows that IRG1 is expressed in atherosclerotic plaques and its deficiency increases plaque burden. Conversely, supplementing the IRG1–itaconate axis with 4-OI induces beneficial remodeling of advanced atherosclerotic plaques in mice and reduces CVD-associated inflammation in human immune cell populations. These findings underscore the therapeutic promise of targeting the IRG1–itaconate pathway for the treatment of CVD. The study also shows that IRG1 is expressed in myeloid cells of human and mouse atherosclerotic plaques, yet its expression wanes with disease progression. Loss-of-function studies in mouse models of atherosclerosis demonstrate that global and hematopoietic Irg1 deficiency increase atherosclerotic burden, plaque lipid content, and indices of plaque instability. Mechanistically, Irg1 deficiency increases NET formation, which acts as a priming signal for the NLRP3 inflammasome in macrophages. In turn, Irg1-def