# Quercetin Inhibits the Progression of Gastric Cancer Through the AKT/MAPK Signaling Pathway

## TL;DR

Quercetin, a compound from Epimedium, inhibits gastric cancer growth by targeting the AKT/MAPK pathway and reducing tumor volume in mice without toxicity.

## Contribution

Quercetin's antitumor mechanism is elucidated through its precise targeting of SERPINE1 and modulation of the AKT/MAPK signaling pathway in gastric cancer.

## Key findings

- Quercetin inhibits gastric cancer cell proliferation and migration by suppressing AKT/MAPK signaling and reversing epithelial–mesenchymal transition.
- Quercetin induces apoptosis by upregulating Bax and downregulating Bcl-2 in gastric cancer cells.
- In vivo experiments showed a 78.4% reduction in tumor volume with quercetin treatment and no systemic toxicity.

## Abstract

Gastric cancer (GC) remains a leading cause of cancer-related death, and treatment options for advanced GC are limited. In this study, in vitro and in vivo experiments were performed to evaluate the effects of quercetin on AGS/MGC803 cells. The in vivo efficacy of quercetin was assessed using a BALB/c xenograft model. We identified 137 common targets, with SERPINE1 being the core target. Quercetin inhibits the AKT/MAPK signaling pathway and reverses epithelial–mesenchymal transition by upregulating E-cadherin and downregulating N-cadherin, thus inhibiting cell proliferation and migration. It also induces apoptosis by upregulating Bax expression and downregulating Bcl-2 expression. The in vivo experiments showed that quercetin treatment reduced the tumor volume by 78.4% without systemic toxicity. This study elucidates the multifaceted antitumor mechanism of quercetin derived from Epimedium, providing a promising therapeutic strategy for cancer treatment through precise targeting of SERPINE1.

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.