Abstract

Quercetin inhibits gastric cancer cell proliferation, invasion, migration, and induces apoptosis. • The anti-tumor effects of quercetin are mediated through targeting and downregulating Serpine1. • Quercetin suppresses tumor angiogenesis by reducing angiogenesis-related factors and markers via Serpine1. • Serpine1 is identified as a novel therapeutic target of quercetin in gastric cancer. Background Gastric cancer (GC) is one of the most common malignancies, characterized by high mortality and recurrence rates. Quercetin, a natural flavonoid found in various herbs and foods, exhibits potential therapeutic effects against GC. This study aims to explore the potential molecular mechanisms of quercetin in the treatment of GC. Methods Bioinformatic analyses were performed using the TCGA-STAD dataset to evaluate SERPINE1 expression, prognosis, angiogenesis-related pathway enrichment, and correlations with angiogenic factors. Molecular docking was employed to predict the binding affinity between quercetin and Serpine1, followed by validation using cellular thermal shift assay (CETSA). Cell proliferation and cytotoxicity were assessed by CCK-8 assays in GC cells and normal gastric epithelial GES-1 cells, and IC50 values were calculated. Serpine1 overexpression and siRNA-mediated knockdown were performed to investigate its functional role. Colony formation assays were used to evaluate clonogenic ability, apoptosis was analyzed by flow cytometry, and Transwell and wound healing assays were used to assess invasion and migration. Tube formation assays were conducted to examine angiogenic potential in HUVECs. Western blotting and qPCR were used to detect Serpine1, angiogenesis-related genes (VEGFA, FGF-2, FGF-7), and HUVEC angiogenesis markers (VEGFR-2, CD31, VE-cadherin). VEGFA secretion in cell supernatants was quantified by ELISA. Results Bioinformatic analysis showed that Serpine1 was highly expressed in GC tissues, associated with poor prognosis, and positively correlated