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Rationale:The glycolytic enzyme pyruvate kinase muscle 2 (PKM2) is upregulated in monocytes/macrophages of patients with atherosclerotic coronary artery disease. However, the role of cell type-specific PKM2 in the setting of atherosclerosis remains to be defined.Objective:We determined whether myeloid cell-specific PKM2 regulates efferocytosis and atherosclerosis.Methods and Results:We generated novel myeloid cell-specific PKM2-/-mice on Ldlr-deficient background (PKM2mye-KOLdlr-/-). Controls were littermate PKM2WTLdlr-/-mice. To rule out sex-based differences, male and female mice were placed on a high-fat "Western" diet for 14 weeks, starting at eight weeks. PKM2 was upregulated in macrophages of Ldlr-/-mice fed the Western diet compared with a control chow diet. Myeloid cell-specific deletion of PKM2 led to a significant reduction in lesions in the whole aorta and aortic sinus despite high cholesterol and triglyceride levels. Furthermore, we found decreased macrophage content in the lesions of myeloid cell-specific PKM2-/-mice associated with decreased MCP-1 levels in plasma, reduced transmigration of macrophages in response to MCP-1, and impaired glycolytic rate. Macrophages isolated from myeloid-specific PKM2-/-mice fed the Western diet exhibited reduced expression of pro-inflammatory genes, including MCP-1, IL-1β, and IL-12. Myeloid cell-specific PKM2-/-mice exhibited reduced apoptosis concomitant with enhanced macrophage efferocytosis and upregulation of LRP1 in macrophages in vitroand atherosclerotic lesions in vivo. Silencing LRP1 in PKM2-deficient macrophages restored inflammatory gene expression and reduced efferocytosis. As a therapeutic intervention, inhibiting PKM2 nuclear translocation using a small molecule reduced glycolytic rate, enhanced efferocytosis, and reduced atherosclerosis in Ldlr-/-mice.Conclusion:Genetic deletion or limiting PKM2 nuclear translocation in myeloid cells reduces atherosclerosis by suppressing inflammation and enhancing efferocytosis.