Serum-based untargeted metabolomics reveals the therapeutic mechanism of asiatic acid against atherosclerosis in ApoE-/- mice.

Atherosclerosis (AS) is a leading cause of cardiovascular morbidity and mortality worldwide. This study investigated the protective effects and underlying mechanisms of asiatic acid (AA), a bioactive triterpenoid from Centella asiatica, in high-fat diet (HFD)-fed ApoE-/- mice and in ox-LDL-stimulated RAW264.7 macrophages. In vivo, AA, particularly at the high dose, was associated with reduced aortic atherosclerotic lesions and attenuated hepatic steatosis, accompanied by an improved serum lipid profile (lower TC, TG, and LDL-C; higher HDL-C) and by attenuated systemic inflammation (IL-6, IL-1β, and TNF-α) and oxidative stress. Mechanistically, AA was associated with upregulation of the PPARγ/LXRα/ABCG1 axis in the liver; consistently, in ox-LDL-induced macrophage-derived foam cells, AA dose-dependently reduced intracellular total and free cholesterol in parallel with restoration of the same PPARγ/LXRα/ABCG1 axis, findings that may reflect improved macrophage cholesterol efflux. Untargeted serum metabolomics further showed that AA reversed a focused set of disease-associated metabolites enriched in pro-inflammatory arachidonic acid-derived oxylipins (e.g., 12R-HETE, 15(S)-HPETE, leukotriene B4, and PGE2-related metabolites). Collectively, these findings suggest that AA exerts multi-target anti-atherosclerotic activity, integrating lipid-regulating, antioxidant, and anti-inflammatory actions, and support its potential as a candidate agent for the prevention and management of atherosclerotic cardiovascular disease.