Mechanism of Red Yeast Rice in the Improvement of Atherosclerosis in Apolipoprotein E-deficient Mice Explored Through Metabolomics Combined with Serum Pharmacochemistry and Network Pharmacology.

Red Yeast Rice (RYR), the fermentation of cooked rice kernels with Monascus purpureus, has been traditionally and increasingly applied to alleviate atherosclerosis (AS). Nonetheless, the precise mechanisms underlying its therapeutic effects in AS treatment remain elusive. Metabolomics combined with serum pharmacochemistry and network pharmacology was utilized to explore the potential molecular mechanisms by which RYR improves AS. RYR showed a significant inhibitory effect on metabolic dysfunction in mice. Specifically, through metabolomics analysis, 45 metabolic biomarkers were identified, which are associated with 5 metabolic pathways, particularly arachidonic acid metabolism. Serum pharmacochemistry identified 11 absorbed constituents of RYR that entered the bloodstream. Subsequent correlation analysis determined that 10 constituents may serve as bioactive ingredients significantly associated with the metabolic biomarkers. Network pharmacology identified 5 core targets and enriched 129 representative pathways, among which the PI3K/AKT signaling pathway received the highest score. Molecular docking verified that there existed strong binding energy between the absorbable components and pivotal targets. The pharmacodynamic evaluation results verified that the down-regulation of PI3K and p-AKT expressions in the PI3K/AKT pathway served as the underlying mechanism of RYR in addressing AS. These findings underscore the pharmacodynamic components, pivotal targets, and pathways of RYR in AS treatment, as well as the development of functional foods involving RYR.