Abstract
Background: Gastric cancer (GC) remains a leading cause of cancer-related mortality, with limited treatment options for advanced stages. This study systematically investigated the molecular mechanisms of quercetin, an active compound from Epimedium, against GC using network pharmacology and experimental validation. Methods: Active compounds were screened from Epimedium. GC targets from GeneCards and Epimedium targets were analyzed for overlap. Molecular docking was conducted using AlphaFold-predicted structures. Serpin family E member 1 (SERPINE1) expression, prognostic value, and immune correlations were analyzed using The Cancer Genome Atlas data. In vitro assays were performed to evaluate quercetin's effects on AGS/MGC803 cells. BALB/c xenograft models were used to assess in vivo efficacy. Results: We identified 137 shared targets, with SERPINE1 as the core target. SERPINE1 was overexpressed in GC and correlated with poor prognosis and M2 macrophage infiltration. In vitro, quercetin dose-dependently inhibited cell proliferation, suppressed migration, and induced apoptosis through increasing Bax while decreasing Bcl-2 expression. It also inhibited AKT/MAPK signaling and reversed epithelial-mesenchymal transition by upregulating E-cadherin and downregulating N-cadherin. In vivo, quercetin treatment led to a 78.4% reduction in tumor volume without causing systemic toxicity. Conclusion: This study elucidated the multifaceted antitumor mechanisms of Epimedium-derived quercetin, which orchestrates dual suppression of tumor proliferation and immune microenvironment regulation through precise targeting of SERPINE1, offering a promising therapeutic strategy for cancer treatment.