Licochalcone C suppresses gastric cancer progression and enhances 5-FU chemosensitivity by targeting RAC3-mediated PI3K-AKT-mTOR signaling

Background : Gastric cancer remains a leading cause of cancer-related mortality worldwide, with limited sensitivity to 5-fluorouracil (5-FU) representing a major obstacle to effective chemotherapy. Licochalcones, bioactive chalcones derived from licorice, have demonstrated broad-spectrum anticancer activities, yet the role of Licochalcone C in enhancing 5-FU sensitivity in gastric cancer remains unexplored. Purpose : This study aimed to investigate the antitumor effects of Licochalcone C on gastric cancer and evaluate its potential to enhance 5-FU chemosensitivity, along with elucidating the underlying molecular mechanisms. Study design : The antitumor and chemosensitizing effects of Licochalcone C were systematically evaluated using human gastric cancer cell lines, patient-derived organoids, clinical specimens, and a mouse xenograft model. Methods : Cell proliferation, colony formation, migration, invasion, and cell cycle distribution were assessed by standard assays. Biotin-labeled Licochalcone C pull-down with mass spectrometry, molecular docking, cellular thermal shift assay, and co-immunoprecipitation were employed for target identification. Western blot and transcriptomic analyses defined the signaling mechanisms. Results : Licochalcone C inhibited gastric cancer cell proliferation, migration, and invasion while inducing G1 arrest, and markedly enhanced 5-FU sensitivity in cell lines, organoids, and xenograft models. Mechanistically, Licochalcone C directly bound RAC3, suppressing the RAC3-mediated PI3K-AKT-mTOR pathway and downregulating P-glycoprotein. Clinically, RAC3 overexpression correlated with advanced stage, poor survival, and unfavorable chemotherapy response. Conclusion : Licochalcone C functions as a RAC3-targeting chemosensitizer that enhances 5-FU efficacy by inhibiting PI3K-AKT-mTOR signaling and P-glycoprotein expression, supporting its development as a therapeutic adjuvant for gastric cancer.