Medicarpin suppresses gastric cancer growth in association with inhibition of mevalonate pathway-associated cholesterol biosynthesis

Introduction Gastric cancer (GC) is an aggressive malignancy characterized by metabolic reprogramming, including dysregulated cholesterol biosynthesis. Medicarpin (Med), a natural isoflavan isolated from Radix Hedysari , has shown pharmacological potential. However, its anti-GC activity and underlying metabolic mechanisms remain unclear. Materials and Methods The effects of Med on AGS and HGC-27 cell viability, proliferation, colony formation, and migration were evaluated. Antitumor activity and tolerability were evaluated in a nude mouse xenograft model. Integrated untargeted metabolomics and quantitative proteomics identified Med-associated metabolic alterations and potential targets. Western blotting, cholesterol quantification, filipin staining, and exogenous cholesterol rescue assays were performed to further investigate the proposed mechanism. Results Med significantly inhibited AGS and HGC-27 cell viability, proliferation, colony formation, and migration in a concentration- and time-dependent manner, with minimal cytotoxicity toward normal gastric mucosal GES-1 cells. In xenografts, Med reduced tumor volume and weight without significant body weight loss or histopathological injury in major organs. Multi-omics analyses revealed extensive metabolic remodeling, with marked suppression of lipid, steroid, and primary bile acid biosynthesis. Proteomics and Western blotting showed that Med downregulated key enzymes in the mevalonate pathway, including mevalonate kinase (MVK), 3-hydroxy-3-methylglutaryl-CoA synthase 1 (HMGCS1), and lanosterol synthase (LSS), accompanied by reduced intracellular cholesterol levels. Exogenous cholesterol supplementation partially reversed Med-induced inhibition of GC cell viability, proliferation, and colony formation. Conclusion Med inhibits GC growth in association with the downregulation of MVK, HMGCS1, and LSS and the inhibition of mevalonate pathway-mediated cholesterol biosynthesis. These findings suggest that Med may represent a potential natural compound for targeting lipid metabolic reprogramming in GC.