Quercetin Alleviates Endothelial Dysfunction in Atherosclerosis by Inhibiting Ferroptosis Through PACS2/HMOX-1 Pathway

Atherosclerosis is a leading cause of worldwide cardiovascular morbidity and mortality, and endothelial ferroptosis has emerged as a key mechanism in driving vascular injury. This study aimed to investigate whether quercetin (QCT), a natural dietary flavonoid with potent anti-oxidant activity, protects against atherosclerosis-associated endothelial dysfunction by modulating ferroptosis. In order to test this, ApoE[Formula: see text] mice fed a high-fat diet were treated with QCT or ferrostatin-1, and their aortic plaque burden, stability, and macrophage infiltration were then assessed. To evaluate ferroptosis, human umbilical vein endothelial cells (HUVECs) were exposed to oxidized low-density lipoprotein (Ox-LDL), with or without QCT, and their reactive oxygen species (ROS), Fe[Formula: see text] accumulation, and heme oxygenase-1 (HMOX-1) expression were measured. While functional assays examined endothelial barrier integrity and monocyte adhesion, gene modulation studies explored the role of phosphofurin acidic cluster sorting protein 2 (PACS2). QCT treatment markedly reduced plaque area, necrotic core size, and macrophage infiltration while enhancing plaque stability. In vitro, QCT suppressed Ox-LDL-induced ferroptosis by decreasing ROS and Fe[Formula: see text] levels and downregulating HMOX-1 to thereby restore endothelial integrity and reduce monocyte adhesion. Mechanistically, QCT restored PACS2 expression suppressed by Ox-LDL. However, PACS2 knockdown or HMOX-1 activation abrogated QCT’s protective effects. These findings identify QCT as a promising dietary anti-oxidant that mitigates atherosclerosis via the PACS2-HMOX-1 ferroptosis pathway.