The study investigates the therapeutic potential of the IRG1-itaconate axis in protecting against cholesterol-induced inflammation and atherosclerosis. Single-cell RNA sequencing (scRNA-seq) revealed that *IRG1* is up-regulated in human coronary atherosclerotic lesions and mouse atherosclerotic plaques, particularly in 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, absence of *Irg1* increases macrophage lipid accumulation and accelerates inflammation by enhancing neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3 inflammasome in macrophages, leading to increased IL-1β release. Conversely, supplementation with 4-octyl itaconate (4-OI), a derivative of itaconate, beneficially remodels advanced plaques and reduces lesional IL-1β levels in mice. In a human ex vivo systems-immunology approach, 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 axis in atherosclerosis.The study investigates the therapeutic potential of the IRG1-itaconate axis in protecting against cholesterol-induced inflammation and atherosclerosis. Single-cell RNA sequencing (scRNA-seq) revealed that *IRG1* is up-regulated in human coronary atherosclerotic lesions and mouse atherosclerotic plaques, particularly in 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, absence of *Irg1* increases macrophage lipid accumulation and accelerates inflammation by enhancing neutrophil extracellular trap (NET) formation and NET-priming of the NLRP3 inflammasome in macrophages, leading to increased IL-1β release. Conversely, supplementation with 4-octyl itaconate (4-OI), a derivative of itaconate, beneficially remodels advanced plaques and reduces lesional IL-1β levels in mice. In a human ex vivo systems-immunology approach, 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 axis in atherosclerosis.