Bioorganic chemistry · 2026
Quercetin inhibits gastric cancer growth and enhances T cells immunity by modulating the PI3K-AKT signaling pathway.
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Liu Yali, Kang Xiaojuan, Wang Jiaxuan, Zhou Xinyang, Tan Wushuang, Kang Tingting, Shi Wengui, Zhang Dekui
Аннотация
BACKGROUND: Quercetin, a flavonoid derived from astragalus and other medicinal plants, exhibits anti-cancer activity; however, its mechanisms in gastric cancer, especially regarding tumor immunity, remain incompletely understood. The aim of this study is to elucidate the mechanism of quercetin against gastric cancer.
METHODS: Quercetin was evaluated in vitro for the effects on proliferation, apoptosis, cell cycle, mitochondrial potential, and morphology in MKN-45, AGS and normal GES-1 cells. Its efficacy and safety were assessed in vivo using a xenograft model. A "gastric cancer cells + T cells" co-culture system was established to examine quercetin's influence on T cell function. Target prediction employed network pharmacology, molecular docking, and molecular dynamics simulations, with validation via PD-L1 knockdown and PI3K overexpression rescue.
RESULTS: Quercetin significantly inhibited MKN-45 proliferation, induced G0/G1 arrest, and promoted apoptosis, accompanied by mitochondrial damage, loss of membrane potential, downregulation of BCL-2, and upregulation of BAX, CytC, cleaved Caspase-9, and cleaved Caspase-3. In vivo, quercetin reduced tumor growth, decreased Ki-67, increased tumor apoptosis and peripheral CD8+ T cells, with no apparent organ toxicity. In co-culture, quercetin enhanced CD8+ T cell cytotoxicity, increasing granzyme B, perforin, IL-2, and IFN-γ. Mechanistically, quercetin bound PD-L1, reduced its protein expression without affecting mRNA, and suppressed the PI3K-AKT signaling pathway.
CONCLUSION: Quercetin exhibited a dual mechanism: it directly suppressed gastric cancer cell proliferation and induced mitochondria-mediated apoptosis, while also enhancing CD8+ T cell cytotoxicity. Its anti-cancer mechanism involved modulation of PD-L1 protein expression and suppression of the PI3K-AKT signaling pathway. These findings supported the feasibility of quercetin as a potential therapeutic candidate for gastric cancer.
METHODS: Quercetin was evaluated in vitro for the effects on proliferation, apoptosis, cell cycle, mitochondrial potential, and morphology in MKN-45, AGS and normal GES-1 cells. Its efficacy and safety were assessed in vivo using a xenograft model. A "gastric cancer cells + T cells" co-culture system was established to examine quercetin's influence on T cell function. Target prediction employed network pharmacology, molecular docking, and molecular dynamics simulations, with validation via PD-L1 knockdown and PI3K overexpression rescue.
RESULTS: Quercetin significantly inhibited MKN-45 proliferation, induced G0/G1 arrest, and promoted apoptosis, accompanied by mitochondrial damage, loss of membrane potential, downregulation of BCL-2, and upregulation of BAX, CytC, cleaved Caspase-9, and cleaved Caspase-3. In vivo, quercetin reduced tumor growth, decreased Ki-67, increased tumor apoptosis and peripheral CD8+ T cells, with no apparent organ toxicity. In co-culture, quercetin enhanced CD8+ T cell cytotoxicity, increasing granzyme B, perforin, IL-2, and IFN-γ. Mechanistically, quercetin bound PD-L1, reduced its protein expression without affecting mRNA, and suppressed the PI3K-AKT signaling pathway.
CONCLUSION: Quercetin exhibited a dual mechanism: it directly suppressed gastric cancer cell proliferation and induced mitochondria-mediated apoptosis, while also enhancing CD8+ T cell cytotoxicity. Its anti-cancer mechanism involved modulation of PD-L1 protein expression and suppression of the PI3K-AKT signaling pathway. These findings supported the feasibility of quercetin as a potential therapeutic candidate for gastric cancer.