Abstract: Objective To investigate the molecular mechanism of quercetin in the treatment of heart failure (HF) based on network pharmacology and molecular docking. Methods Quercetin and HF-related targets were obtained using TCMSP, PharmMapper, CTD and GeneCards databases, and quercetin-HF intersection targets were obtained through the online website Venn; the protein interaction network was constructed and imported into Cytoscape 3.7.2 to identify the core targets of quercetin in the treatment of HF. GO and KEGG pathway enrichment analyses were performed using R package, and molecular docking was performed using Auto Dock Vina. The protein levels of AKT1, phospho-AKT (Ser473), eNOS, MMP9, and caspase-3 in quercetin-treated HF cell models were detected using protein immunoblotting. Results We identified 80 quercetin-HF intersectional targets (AKT1, CASP3, MAPK1, MMP9, and MAPK8) and 5 core targets of quercetin for treatment of HF. GO analysis suggested that the therapeutic effect of quercetin for HF was mediated mainly by such biological processes as responses to peptide hormones, phosphatidylinositol-mediated signalling, responses to lipopolysaccharides, responses to molecules of bacterial origin and regulation of inflammatory responses. KEGG pathway enrichment analysis identified lipid and atherosclerosis pathway, proteoglycans in cancer, PI3K-AKT signaling pathway, diabetic cardiomyopathy and MAPK signaling pathway as the most significantly enriched signaling pathways. Molecular docking showed a good binding activity of quercetin to the 5 core targets. The results of protein immunoblotting showed that 100 μmol/L quercetin significantly reduced AKT1, phospho-AKT (Ser473), eNOS, MMP9 and caspase-3 levels in the cell models of HF (P<0.01). Conclusion Quercetin improves the pathological changes in HF possibly by regulating the AKT1-eNOS-MMP9 pathway to inhibit cell apoptosis.

Key words: quercetin; heart failure; molecular docking; network pharmacology