Uncovering the Anti-Atherosclerotic Effect of Isoquercitrin via Microbiome Metabolic Modulation and Network Pharmacology

Atherosclerosis (AS) is increasingly recognized as a disease influenced not only by lipid metabolism and inflammation but also by the gut microbiota and their bioactive metabolites. Isoquercitrin (ISO), a natural flavonoid with food-medicine homology, has shown promising antiatherosclerotic potential, yet its underlying mechanisms remain unclear. In this study, ISO administration significantly reduced plaque burden, improved lipid profiles, and restored gut microbial balance by enriching beneficial taxa, such as Lactobacillus, Dubosiella, and Eubacterium_R. These taxa are associated with beneficial microbial functions, including β-glucosidase activity, which facilitates ISO deglycosylation into cis-dihydroquercetin, 3,4-dihydroxyphenylpropionaldehyde (3,4-DHPPAL). ISO also reprogrammed tryptophan metabolism, promoting the production of indole derivatives (e.g., indolepyruvate, tryptophanol, and 5-methoxyindoleacetate) and suppressing the kynurenine pathway, thereby enhancing intestinal barrier integrity. Notably, network pharmacology and molecular docking identified HSP90β as a plausible host target of ISO and its metabolites (quercetin and cis-dihydroquercetin). Correlation analysis further linked the HSP90β expression to key enzymes in the tryptophan pathway, suggesting an integrated regulatory role. These findings suggest that ISO alleviates AS through a gut microbiota-tryptophan metabolism-HSP90β axis, offering new mechanistic insights into the therapeutic potential of natural compounds for cardiovascular diseases.