Transcription Factor MAFG Protects Mice from High-Fat Diet–Induced Atherosclerosis by Inhibiting Endothelial Cell Apoptosis

BACKGROUND Atherosclerosis is a serious cardiovascular condition characterised by lipid accumulation and plaque formation. Endothelial cell apoptosis is a critical initiating event in atherosclerosis. The transcription factor MAFG has been shown to inhibit apoptosis in human umbilical vein endothelial cells (HUVECs) in vitro , but its specific role in atherosclerosis progression in mice and the related signalling pathway remain unclear. METHODS We generated endothelial-specific MAFG transgenic mice and maintained them on a high-fat diet to assess plaque formation. MAFG was overexpressed in HUVECs treated with palmitic acid (PA), and PI3K–AKT/NRF2/MAFG signalling pathway rescue experiments were performed. We further compared MAFG expression in atherosclerotic plaques from patients and controls. Proteomic analysis and Gene Set Enrichment Analysis were conducted to elucidate the molecular mechanisms downstream of MAFG. RESULTS Endothelial-specific overexpression of MAFG in mice significantly attenuated atherosclerotic plaque formation. MAFG inhibited PA-induced apoptosis in HUVECs. Treatment of HUVECs with a PI3K–AKT agonist inhibited apoptosis, while AKT knockdown promoted it; these effects were reversed by MAFG and NRF2 knockdown and overexpression, respectively. MAFG expression was significantly elevated in the endothelial cells proximal to atherosclerotic plaques. Proteomic profiling revealed that MAFG induces metabolic reprogramming, characterised by the concurrent suppression of mitochondrial respiration and upregulation of antioxidant defences, thereby mitigating oxidative stress and inhibiting endothelial apoptosis. CONCLUSIONS MAFG serves as a critical protective factor in atherosclerosis by promoting endothelial cell survival via antioxidant metabolic reprogramming. Thus, targeting the MAFG signalling axis may offer a novel early-stage intervention for atherosclerosis.