Mechanism of ginkgetin in inducing immunogenic cell death of gastric cancer cells by inhibiting the STAT3 signaling.

Gastric cancer (GC) ranks among the most prevalent and lethal malignancies worldwide. Conventional therapeutic modalities exhibit limited clinical efficacy and are accompanied by severe adverse effects. Consequently, there remains an urgent unmet clinical need for effective therapeutic strategies. Ginkgetin (Gin), a major biflavonoid compound isolated from the leaves of Ginkgo biloba L., has been demonstrated to exert anti-tumor activities against a variety of cancer types. Nevertheless, the biological effects and underlying mechanisms of ginkgetin in GC have rarely been reported. Therefore, the present study seeks to investigate the therapeutic potential and molecular mechanisms of ginkgetin in the management of GC. In vitro experiment, MTT assay, EdU assay, transwell assay, ELISA, and flow cytometry were employed to investigate the impacts of Gin on the proliferation, migration, apoptosis, mitochondrial damage, and immunogenic cell death (ICD) of GC cells. Subsequently, in vivo experiment, the immunomodulatory and anti-tumor activities of Gin were evaluated using ELISA and flow cytometry. Finally, network pharmacology and molecular docking analyses were performed to identify the core targets and pathways underlying Gin-mediated therapeutic effects against GC, with further validation conducted via vitro experiments. In vitro assays demonstrated that Gin potently suppressed the proliferation and migration of gastric cancer cells, promoted intracellular reactive oxygen species (ROS) production,and triggered cancer cell apoptosis. Most notably, Gin was capable of eliciting ICD in gastric cancer cells. In vivo experimental results revealed that Gin could activate anti-tumor immune responses, reverse the immunosuppressive tumor microenvironment (TME), thereby boosting the overall anti-tumor immune response and ultimately inhibiting tumor progression. Collectively, network pharmacology analyses and in vitro validation experiments indicated that Gin exerts its therapeutic efficacy against gastric cancer by blocking the phosphorylation of STAT3. By targeting STAT3 to trigger ICD in gastric cancer cells, ginkgetin activates anti-tumor immune responses and reverses the immunosuppressive TME, thereby providing novel insights into the pharmacological mechanisms underlying its therapeutic effects against GC.