Metformin as a multi-target modulator of atherosclerosis: integrated regulation of Nrf2/KLF2, mitochondrial homeostasis, inflammation, ferroptosis, and innate immunity
Abstract
Objectives: Atherosclerosis (AS) is a chronic inflammatory vascular disorder driven by endothelial dysfunction, oxidative stress, lipid dysregulation, mitochondrial injury, and maladaptive immune activation. Metformin, the first-line therapy for type 2 diabetes, has vasculoprotective effects beyond glycemic control. This review summarizes current evidence on metformin as a multi-target modulator of AS through regulation of nuclear erythroid 2-related factor 2 (Nrf2)/Krüppel-like factor 2 (KLF2) signaling, AMP-activated protein kinase (AMPK)/sirtuin-1 pathways, cyclic GMP-AMP synthase and stimulator of interferon genes (cGAS-STING) signaling, mitochondrial homeostasis, lipid metabolism, and inflammation.
Methods: Relevant studies were identified through PubMed, Web of Science, Google Scholar, and China National Knowledge Infrastructure databases, focusing on the effects of metformin on atherosclerosis and related pathways involving oxidative stress, mitochondrial function, ferroptosis, inflammation, and innate immunity.
Key findings: Metformin enhances antioxidant defenses by activating Nrf2 through Kelch-like ECH-associated protein 1 degradation and increasing cytoprotective mediators such as heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1. It also modulates cGAS-STING signaling and promotes AMPK-mediated KLF2 activation, thereby improving endothelial quiescence, increasing endothelial nitric oxide synthase-derived nitric oxide, and suppressing inflammatory signaling…
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