Wogonin Attenuates Atherosclerosis via KLF11‐Mediated Suppression of PPARα‐YAP1‐Driven Glycolysis and Enhancement of ABCA1/G1‐Mediated Cholesterol Efflux

Abstract

Atherosclerosis, a chronic inflammatory disorder and leading cause of cardiovascular disease, is characterized by macrophage-derived inflammation and foam cell formation. Emerging evidence suggests that metabolic reprogramming of macrophages represents a promising therapeutic approach for atherosclerosis management. In this study, the therapeutic potential of wogonin, a bioactive flavonoid isolated from Scutellaria baicalensis, in modulating macrophage metabolism and attenuating atherogenesis is investigated. Wogonin reduces lesion size and plaque vulnerability, accompanied by a reduction in foam cell formation and inflammation. Mechanistically, wogonin reprogrammes macrophage metabolism from glycolysis to fatty acid oxidation (FAO) by activating the PPARα-CPT1α pathway and acts as a mitochondrial protector by activating PPARα. Wogonin also promotes the KLF11 expression and KLF11 knockout exacerbated atherosclerosis and abolishes the inhibitory effect of wogonin on glycolysis and atherosclerosis. KLF11 forms a transcriptional complex with PPARα and YAP1, serving both as a brake on PPARα-YAP1-mediated glycolysis and a transcriptional activator of ABCA1/G1. Collectively, wogonin reprograms macrophage metabolism from glycolysis to FAO through activation of the PPARα-KLF11-YAP1 pathway, thereby reducing inflammation and foam cell formation, ultimately attenuating atherogenesis.