Abstract

Background The phagocytic function of macrophages is pivotal in regulating vascular inflammation and the progression of atherosclerosis (AS). Si-Miao-Yong-An Decoction (SMYAD), a traditional Chinese multi-herbal remedy, has been used in the treatment of vascular inflammation and AS. However, its impact on the phagocytic activity of macrophages remains unexplored. Methods ApoE −/− mice were divided into normal control groups. Model, SMYAD-treated (35.1 or 70.2 g/kg), colchicine-treated (0.102 m g/kg) ( n  = 6), and fed a high-fat diet (HFD) for 10 weeks in vivo. Several parameters were assessed, including aortic plaque area, lipid accumulation, inflammatory cytokine levels, and macrophage efferocytosis. Potential core targets of SMYAD in restoring macrophage efferocytosis were predicted through network pharmacology. In vitro, RAW264.7 macrophages were exposed to oxidized low-density lipoprotein (ox-LDL) and SMYAD-containing serum. Macrophage efferocytosis was evaluated via Western blot (WB), RT-qPCR, and co-culture assays with apoptotic cells. Predicted targets were further validated through in vitro experiments. Results SMYAD reduced lipid deposition and plaque area in ApoE −/− mice, lowered the levels of inflammatory cytokines, and restored macrophage efferocytosis. Network pharmacology analysis identified PPAR-γ as the key mediator of SMYAD's effects on macrophage efferocytosis. In cell-based assays, SMYAD upregulated MerTK expression, enhanced macrophage efferocytosis, and, through siRNA interference, confirmed that this effect is mediated via the PPAR-γ pathway. Conclusions This study, combining in vivo and in vitro experiments with network pharmacology, elucidates that SMYAD restores macrophage efferocytosis and mitigates vascular inflammation via the PPAR-γ/MerTK signaling pathway, offering potential therapeutic benefits for AS.