Journal of ethnopharmacology · 2025
Oleanolic acid 28-O-β-D-glucopyranoside alleviates TNBS-induced ulcerative colitis in rat by regulating Nrf2/x-CT/GPX4-mediated ferroptosis.
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Wang Caixia, Li Zhuoqiao, Liu Linxuan, Jia Wang, Geng Xiaoyu, Liu Hanlin, Wang Cuizhu, Wu Yuanyuan, Lin Hongqiang, Liu Jinping
Аннотация
ETHNOPHARMACOLOGICAL RELEVANCE: 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.
AIM OF THE STUDY: To explore the underlying mechanism of OAG regulating ferroptosis to alleviate UC.
MATERIALS AND METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
AIM OF THE STUDY: To explore the underlying mechanism of OAG regulating ferroptosis to alleviate UC.
MATERIALS AND METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.