Rosmarinic Acid Targets AKR1B1 to Ameliorate Atherosclerosis via Vascular Endothelial Cell Energy Metabolism Regulation

Atherosclerosis (AS), a chronic cardiovascular disease, originates from endothelial dysfunction, a process closely linked to cellular energy metabolism. While rosmarinic acid (RA) exhibits protective cardiovascular effects, its precise mechanism against AS remains undefined. This study demonstrates that RA alleviates AS in ApoE^-/- mice, as evidenced by reduced aortic plaques, enhanced CD31 expression, and improved serum NO and ET-levels. Integrating network pharmacology and experimental validation, we identified Aldo-keto reductase family 1 member B1 (AKR1B1) as a direct functional target of RA. Mechanistically, RA downregulated AKR1B1, thereby activating the SIRT3/PFKFB3 axis. In Ox-LDL-induced HUVECs, RA enhanced viability, reduced ROS, and boosted energy metabolism, indicated by elevated ECAR, OCR, and levels of G-6-P, F-6-P, and ATP. Crucially, RA rescued endothelial injury induced by AKR1B1 overexpression via this pathway. Our findings establish that RA protects against AS by directly targeting AKR1B1 to restore endothelial energy homeostasis through the AKR1B1/SIRT3/PFKFB3 signaling axis, offering a novel therapeutic strategy.