Dapagliflozin binds PRMT7 to inhibit p38 MAPK phosphorylation and macrophage foam cell formation in atherosclerosis.

Dapagliflozin exerts anti-atherosclerotic effects, yet its underlying mechanisms remain incompletely elucidated. In high-fat diet-fed ApoE-deficient mice and ox-LDL-stimulated RAW264.7 foam macrophages, dapagliflozin alleviated aortic atherosclerotic lesions and intracellular lipid accumulation. Proteomic analysis identifies 73 differentially expressed proteins, with upregulated ATP Binding Cassette Subfamily G Member 1 (ABCG1) and downregulated lipoprotein lipase (LPL) in dapagliflozin-treated macrophages. Molecular docking reveals high-affinity binding between dapagliflozin and protein arginine methyltransferase 7 (PRMT7), whose overexpression in plaque foam macrophages is validated by scRNA-seq and immunofluorescence. Functional assays demonstrate that PRMT7 promotes macrophage foam formation and p38 mitogen-activated protein kinase (MAPK) phosphorylation, while dapagliflozin inhibits p38 MAPK activation via targeting PRMT7. Notably, PRMT7 knockdown abolished dapagliflozin's regulatory effects on p38 MAPK, ABCG1, LPL, and foam cell formation. In conclusion, dapagliflozin alleviates atherosclerosis (AS) by binding PRMT7 to suppress p38 MAPK phosphorylation and regulate ABCG1/LPL expression, thereby attenuating macrophage foam formation. These findings uncover the anti-atherosclerotic mechanism of dapagliflozin and contribute to precision therapeutic strategies for AS.