Wogonin Attenuates Atherosclerosis via KLF11‐Mediated Suppression of PPARα‐YAP1‐Driven Glycolysis and Enhancement of ABCA1/G1‐Mediated Cholesterol Efflux
Chuanrui Ma, Yunqing Hua, Shu Yang, Yun Zhao, Wei Zhang, Yaodong Miao, Jing Zhang, Boxuan Feng, Guobin Zheng, Lan Li, Zhihao Liu, Han Zhang, Mingjun Zhu, Xiumei Gao, Guanwei Fan
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.