Medicarpin suppresses gastric cancer growth in association with inhibition of mevalonate pathway-associated cholesterol biosynthesis
Abstract
IntroductionGastric 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 MethodsThe 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.ResultsMed 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.ConclusionMed 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.
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BibTeX
@article{huang2026medicarpin,
title = {{Medicarpin suppresses gastric cancer growth in association with inhibition of mevalonate pathway-associated cholesterol biosynthesis}},
author = {Kaimeng Huang and Shan Huang and Xing Wang and Yuxin Liu and Chunyuan Guo and Ming Yang and Jiangshan Zhang and Jing Cao and Wenqiang Xu and Tao Zhou and Minchao Deng and Jing Ouyang and Fangfang Tou and Zhi Zheng},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.2004034},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.2004034},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Medicarpin suppresses gastric cancer growth in association with inhibition of mevalonate pathway-associated cholesterol biosynthesis
AU - Kaimeng Huang
AU - Shan Huang
AU - Xing Wang
AU - Yuxin Liu
AU - Chunyuan Guo
AU - Ming Yang
AU - Jiangshan Zhang
AU - Jing Cao
AU - Wenqiang Xu
AU - Tao Zhou
AU - Minchao Deng
AU - Jing Ouyang
AU - Fangfang Tou
AU - Zhi Zheng
PY - 2026
DA - 2026/11/05
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.2004034
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.2004034
AB - IntroductionGastric 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 MethodsThe 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.ResultsMed 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.ConclusionMed 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.
SN - 1663-9812
ER -