Quercetin induces immunogenic cell death against gastric cancer by targeting NR3C1

Ting Liu; Ying Wang; Min Peng; Fanghua Qi; Yuan Liu; Hailing Ding; Fang Chen

doi:10.1016/j.toxicon.2025.108477

Quercetin induces immunogenic cell death against gastric cancer by targeting NR3C1

Toxicon. 2025 Jul 3:265:108477. doi: 10.1016/j.toxicon.2025.108477. Online ahead of print.

Authors

Ting Liu¹, Ying Wang², Min Peng³, Fanghua Qi³, Yuan Liu³, Hailing Ding⁴, Fang Chen⁵

Affiliations

¹ Shandong University of Traditional Chinese Medicine, Jinan, 250013, Shandong, PR China; Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, PR China; Medical College, Qilu Institute of Technology, Jinan, 250200, Shandong, PR China.
² Medical College, Qilu Institute of Technology, Jinan, 250200, Shandong, PR China.
³ Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, PR China.
⁴ Medical College, Qilu Institute of Technology, Jinan, 250200, Shandong, PR China. Electronic address: 15066139770@163.com.
⁵ Department of Traditional Chinese Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, PR China. Electronic address: chenfang7874@163.com.

PMID: 40617261
DOI: 10.1016/j.toxicon.2025.108477

Abstract

Gastric cancer is a major global health issue with limited treatment options. Quercetin, a natural flavonoid, has shown anticancer effects, but its mechanisms and molecular targets in gastric cancer remain unclear. This study aims to evaluate the impact of Quercetin on gastric cancer cells, focusing on its potential target, nuclear receptor subfamily 3 group C member 1 (NR3C1). AGS and MKN45 gastric cancer cells were treated with Quercetin, and cell viability, proliferation, apoptosis, endoplasmic reticulum (ER) stress, and immunogenic cell death (ICD) were assessed using standard assays. PharmMapper was utilized to predict potential targets of Quercetin in gastric cancer cells. The role of NR3C1 was further validated by introducing an NR3C1 overexpression plasmid into Quercetin-treated cells, followed by assessing changes in cellular behavior. A subcutaneous mouse tumor model was established, and the expression of NR3C1, ICD, apoptosis, and ER stress markers was detected by Western blot. Quercetin significantly reduced the viability and proliferation of gastric cancer cells while promoting apoptosis, ER stress and ICD. NR3C1 was identified as a molecular target of Quercetin. Overexpression of NR3C1 counteracted Quercetin's effects on proliferation, apoptosis, ER stress, and ICD in gastric cancer cells, highlighting its key role in mediating these outcomes. The addition of Quercetin inhibited subcutaneous tumor growth. In vivo results also indicated that Quercetin had similar effects on tumor proliferation, apoptosis, ER stress, and ICD as observed in the in vitro experiments. The bioinformatics analysis results show that NR3C1 can promote immune escape. Quercetin exhibits strong anticancer effects in gastric cancer by targeting NR3C1, reducing cell viability and proliferation while inducing ER stress, apoptosis, and ICD. These results highlight NR3C1 as a potential therapeutic target for Quercetin-based gastric cancer treatments.

Keywords: Endoplasmic reticulum stress; Gastric cancer; Immunogenic cell death; NR3C1; Quercetin.