Metformin Attenuates ox‐LDL‐Induced Macrophage Senescence and Inflammation via NR4A1‐Mediated Mitophagy Regulation

ABSTRACT Metformin alleviates oxidized low‐density lipoprotein (ox‐LDL)‐induced macrophage senescence, a key process in atherosclerosis. Our in vitro findings demonstrate that metformin suppresses ox‐LDL‐induced overexpression of the nuclear receptor NR4A1 in macrophages. This inhibition subsequently reduces excessive mitophagy, improves mitochondrial membrane potential and decreases reactive oxygen species (ROS) production. The amelioration of this mitochondrial dysfunction directly attenuated cellular senescence markers and reduced the secretion of inflammatory cytokines. Furthermore, we identified Caveolin‐1 as a critical regulator of metformin's protective effects. Overexpression of Caveolin‐1 was shown to reverse metformin‐mediated improvements in mitochondrial function. These results establish that metformin mitigates macrophage senescence by targeting the NR4A1–mitophagy pathway, with Caveolin‐1 serving as an essential modulator. This NR4A1–mitophagy axis represents a promising therapeutic target, positioning metformin as a potential candidate for slowing atherosclerosis progression by preserving mitochondrial health in macrophages.