Background <p>Atherosclerosis (AS) is a complex vascular disease characterized by lipid accumulation, chronic inflammation, and immune dysregulation. Qinggan Jianpi Formula (QGJP), a traditional Chinese medicinal preparation, is widely used for treating lipid metabolism disorders. However, the mechanisms of action and active components remain unclear. These uncertainties restrict its clinical use and necessitate systematic research to clarify them. This study aims to investigate the therapeutic effects of QGJP on AS and to elucidate the role of suppressing macrophage M1 polarization in this process, mediated by the regulation of lactate transport and the promotion of histone lactylation.</p> Methods <p>In this study, first, major chemical components of QGJP were identified via UHPLC-HRMS. We employed a high-fat diet (HFD) fed ApoE^⁻/⁻ C57BL/6 mice to establish an AS model, along with in vitro models of ox-LDL-induced lipid injury in HUVECs and ox-LDL-induced foam cell formation in THP-1, followed by QGJP treatment. We elucidated the therapeutic effects and underlying mechanisms of QGJP in AS through multiple approaches, including protecting endothelial cells and regulating macrophage polarization.</p> Results <p>QGJP significantly reduced blood lipids, modulated plaque lipid and collagen content, and alleviated aortic pathological damage in AS mice. Moreover, QGJP downregulated the expression of matrix metalloproteinases, adhesion molecules, and chemokines, enhanced endothelial migration capacity, and inhibited monocyte-endothelial adhesion. Further analysis of macrophage polarization phenotypes revealed that QGJP significantly modulated their polarization state. Mechanistically, QGJP suppressed the expression of key glycolytic enzymes while promoting that of FH. Consequently, it reversed the increase in glycolytic activity observed in macrophages during atherosclerosis. Furthermore, QGJP regulated lactate transport by suppressing MCT4 expression. This modulation orchestrated histone H3K18 lactylation, which in turn activated repair-related gene programs in macrophages. Through UHPLC-HRMS analysis, 47 bioactive constituents of QGJP were identified. Experimental validation confirmed that SAA, LA, and CAB effectively inhibited M1 macrophage polarization and activated the expression of proteins related to reparative genes.</p> Conclusions <p>This study establishes the critical role of metabolic reprogramming and epigenetic regulation in AS progression. Our findings suggest that a mechanism whereby QGJP alleviates AS may involve the inhibition of the HIF-1α/MCT4 axis and lactate transport, which regulates histone H3K18 lactylation to promote a reparative macrophage phenotype.</p>