Abstract Body: Systemic inflammation is a key driver of atherosclerotic cardiovascular disease (ASCVD), in part via hypercholesterolemia-induced expansion of hematopoietic stem cells (HSC) that supply proinflammatory myeloid cells to infiltrate plaques. While the metabolic reprogramming of myeloid cells and their precursors has emerged as a critical determinant of this heightened inflammatory state, the underlying molecular regulators remain incompletely defined. Here, we identify the metabolite itaconate, produced from the Krebs cycle enzyme immune-responsive gene 1 (IRG1), as a protective regulator of inflammation in atherosclerosis, constraining maladaptive hematopoiesis and plaque monocyte recruitment through suppression of the interleukin-1 (IL-1) signaling pathway. To interrogate the role of the IRG1-itaconate axis in hypercholesterolemia-driven hematopoietic reprogramming, wild type (WT) and Irg1^–/– mice were rendered hypercholesterolemic via PCSK9 gain-of-function and Western diet feeding for 12 weeks. Compared to WT controls, Irg1 deficiency induced the expansion of HSCs with myeloid-biased differentiation potential, resulting in an increase in granulocyte-monocyte progenitors (GMP) in the bone marrow (BM) and a larger pool of circulating monocytes. Consistent with a direct role for itaconate in regulating HSC fitness, supplementation of itaconate in ex vivo purified HSCs resulted in an increase in cellular quiescence, an indicator of improved hematopoietic health. Single nucleus multiomic RNA- and ATAC-sequencing of BM progenitors revealed enhanced chromatin accessibility at pro-inflammatory gene loci governed by AP-1 and the C/EBP family of transcription factors in Irg1^–/– GMPs, including Il1a and Il1b. Consistent with these epigenomic changes, Irg1^–/– mice exhibited elevated circulating IL-1b levels. Pharmacologic blockade of IL-1 signaling with the IL-1 receptor antagonist anakinra for 4 weeks mitigated the inflammatory and hematopoietic consequences of Irg1 deficiency, reducing myeloid progenitor expansion, Ly6C^hi monocyte recruitment to plaques, and atherosclerosis burden. Collectively, these findings establish the IRG1-itaconate axis as a critical metabolic brake on IL-1-driven inflammatory hematopoiesis and atherogenesis. Our study further elucidates mechanisms linking hypercholesterolemia, cytokine-driven hematopoietic dysregulation, and inflammatory cardiovascular disease risk, highlighting therapeutic promise for immunometabolic restoration in ASCVD.