Pelargonidin-3-O-Glucoside Restores Nitric Oxide Production via Interaction with circHMGCS1 to Ameliorate Endothelial...

Cardiovascular disease is the leading cause of death in type 2 diabetes, driven by vascular endothelial dysfunction. Anthocyanins are promising vasoprotective compounds. Yet, their molecular mechanisms remain unclear. Here, pelargonidin-3-O-glucoside (Pg3G) was identified as the most effective anthocyanin in restoring endothelial function under high-fat/high-glucose stress. Pg3G enhanced nitric oxide production, activated enhanced endothelial nitric oxide synthase, reduced reactive oxygen species levels, and inhibited adhesion molecule expression in endothelial cells. In type 2 diabetic mice, Pg3G improved glucose homeostasis and vascular relaxation. Mechanistically, Pg3G suppressed circHMGCS1, a pathogenic circular RNA that disrupts endothelial homeostasis, thereby reactivating the miR-4521/ARG1 axis. Knockdown of circHMGCS1 reproduced the protective effects of Pg3G, whereas overexpression counteracted them. Molecular docking and dynamics simulations revealed stable binding between Pg3G and circHMGCS1, supporting a direct interaction. These findings identify circHMGCS1 as a novel target of Pg3G and uncover a unique anthocyanin-circRNA regulatory mechanism in diabetic vascular protection.