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. Graphical Oxidized LDL (ox-LDL) induces macrophage senescence characterized by mitochondrial dysfunction and excessive mitophagy. This process leads to increased secretion of proinflammatory cytokines (IL-6, TNF-α, IL-1β). The nuclear receptor NR4A1 plays a key regulatory role in this pathway. Metformin treatment alleviates these effects by modulating mitophagy and restoring mitochondrial function.