Metformin suppresses atherosclerosis by dampening extramedullary myelopoiesis

Impaired cholesterol homeostasis is a major factor contributing to the development and progression of atherosclerosis. Previous studies have shown that metformin, the first-line antidiabetic therapy, has cardioprotective effects in patients with diabetes. However, the antiatherogenic effect of metformin in nondiabetic individuals remains unclear. The aim of this study was to determine the antiatherosclerotic effects of metformin under normoglycemic conditions and, mechanistically, to assess its impact on hematopoietic stem and progenitor cell (HSPC) biology and extramedullary myelopoiesis. Here, we demonstrated that metformin decreased atherosclerotic lesion size, reduced plaque macrophages, and lowered circulating atherogenic Ly6-C^hi monocytes and neutrophil levels in <i>Apoe</i>^-/- mice, independent of blood glucose regulation. Mechanistically, metformin-treated <i>Apoe</i>^-/- mice exhibited increased HSPC retention in the bone marrow and decreased numbers of circulating hematopoietic stem and progenitor cells (HSPCs), along with reduced levels of Ly6-C^hi monocytes and neutrophils in the spleen. Our results indicate that decreased circulating cholesterol and increased expression of the ATP-binding cassette transporter gene <i>Abca1</i> in HSPCs, thereby promoting cholesterol efflux in these cells, are critical factors leading to the suppressed mobilization of HSPCs and myelopoiesis in metformin-treated mice. Collectively, our findings support the use of metformin as an antiatherosclerotic agent under euglycemic conditions. We reveal that this effect is achieved by dampening HSPC mobilization and extramedullary myelopoiesis, providing molecular evidence for metformin's role in reducing macrophage-driven inflammation and, consequently, attenuating atherosclerotic progression.<b>NEW & NOTEWORTHY</b> This study uncovers a novel role for metformin in reducing inflammatory and atherogenic monocytes by dampening extramedullary myelopoiesis, thereby delaying atherosclerosis development under normoglycemic conditions. We demonstrate that metformin suppresses hematopoietic stem and progenitor cell mobilization and reduces macrophage-driven inflammation, providing mechanistic evidence for its antiatherosclerotic potential beyond diabetes management. These findings highlight new therapeutic opportunities for metformin in cardiovascular disease, extending its clinical utility to the prevention of atherosclerosis in nondiabetic individuals.