Wang Caixia, Li Zhuoqiao, Liu Linxuan, Jia Wang, Geng Xiaoyu, Liu Hanlin, Wang Cuizhu, Wu Yuanyuan, Lin Hongqiang, Liu Jinping
School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
College of Basic Medical Sciences, Jilin University, Changchun 130021, China.
J Ethnopharmacol. 2025 Sep 25;353(Pt B):120369. doi: 10.1016/j.jep.2025.120369. Epub 2025 Aug 6.
Panax ginseng C.A. Meyer has been used traditionally for treating gastrointestinal disorders. Oleanolic acid 28-O-β-D- glucopyranoside (OAG), a major pentacyclic triterpenoid in ginseng, has demonstrated the antioxidant and the anti-ulcerative colitis effects in our previous studies. However, whether OAG intervenes UC by alleviating oxidative stress injury through regulating ferroptosis remains unclear.
To explore the underlying mechanism of OAG regulating ferroptosis to alleviate UC.
A TNBS-induced UC rat model, which closely mimics the immunological characteristics of human UC, was established to evaluate the therapeutic efficacy of OAG by analyzing the disease activity index (DAI), colonic macroscopic damage index (CMDI), biochemical indicators, Th17/Treg cell ratio and IL-17 levels, pathomorphological alterations, tight junction proteins (TJs), intestinal epithelial ultrastructure. Subsequently, an integrated multi-omics analysis was conducted to elucidate whether ferroptosis pathways underlie OAG's efficacy against UC and to screen for key candidate genes and proteins, which were further validated using quantitative PCR and western blotting. Finally, molecular docking and the cellular thermal shift assay were performed to confirm the direct binding of OAG to key ferroptosis-related proteins in an RSL3-induced ferroptosis model of Caco-2 cells.
OAG treatment significantly ameliorated UC symptoms, attenuated oxidative stress and inflammatory cell infiltration, reduced Th17/Treg cell ratio and IL-17 levels, and enhanced intestinal epithelial barrier integrity. Ferroptosis inhibition was identified as the crucial mechanism mediating OAG's therapeutic effects, with direct interactions between OAG and key ferroptosis-related proteins (GPX4, NRF2, HO-1, and x-CT) executing its protective effects against UC.
This study demonstrates that OAG effectively ameliorates TNBS- induced UC by modulating Nrf2/x-CT/GPX4-mediated ferroptosis pathway, furthering our understanding of its molecular mechanism and supporting its therapeutic potential for UC treatment.
