Ribes diacanthum Pall modulates bile acid homeostasis and oxidative stress in cholestatic mice by activating the SIRT1/FXR and Keap1/Nrf2 signaling pathways

Alamusi Bayoude; Jiaxin Zhang; Yuanjiang Shen; Akhtolkhyn Tilyek; Chengzhi Chai

doi:10.1016/j.jep.2025.119400

Ribes diacanthum Pall modulates bile acid homeostasis and oxidative stress in cholestatic mice by activating the SIRT1/FXR and Keap1/Nrf2 signaling pathways

J Ethnopharmacol. 2025 Jan 24:119400. doi: 10.1016/j.jep.2025.119400. Online ahead of print.

Authors

Alamusi Bayoude¹, Jiaxin Zhang¹, Yuanjiang Shen¹, Akhtolkhyn Tilyek², Chengzhi Chai³

Affiliations

¹ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China.
² Department of Pharmaceutical Chemistry and Pharmacognosy, Mongolian University of Pharmaceutical Sciences, Ulaanbaatar, 18130, Mongolia.
³ State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, 211198, China; Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, 211198, China. Electronic address: chengzhichai@cpu.edu.cn.

PMID: 39864603
DOI: 10.1016/j.jep.2025.119400

Abstract

Ethnopharmacological relevance: Cholestatic liver injury (CLI) is a pathophysiological syndrome characterized by the accumulation of bile acids (BAs), which leads to significant hepatic dysfunction. This condition is frequently associated with disturbances in BAs homeostasis and the induction of oxidative stress. Ribes diacanthum Pall (RDP), a conventional folk medicinal plant, has been employed in Mongolia, the Inner Mongolia region of China, and other areas for the remediation of hepatic disorders. However, the specific mechanism and chemical composition by which RDP exerts its effects remain unknown.

Aim of the study: The aim of this research was to assess the protective impact of RDP on CLI and probe into the underlying mechanism and pinpoint the active constituents of RDP.

Materials and methods: For this study, a CLI mouse model induced via bile duct ligation (BDL) was used to investigate the hepatoprotective effect of RDP. Mice were administered low, medium, or high doses of RDP for 6 consecutive days, beginning 3 days prior to BDL induction. Subsequently, serum biochemical parameters, hepatic histopathology, and cholestatic markers were analyzed. An HPLC-QTOF-MS/MS analysis was also conducted to identify the prototype constituents in RDP. Furthermore, component-directed network pharmacology was utilized to identify the active constituents, central targets, and signaling cascades of RDP. Eventually, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were adopted to confirm the associated antioxidant enzymes, BAs transporters, and metabolic enzymes. Molecular docking was applied to forecast the binding affinity between the components and core targets.

Results: RDP effectively ameliorated the pathological liver damage and cholestasis in BDL-induced CLI mice. Moreover, 43 components within RDP were identified through HPLC-QTOF-MS/MS analysis. Altogether 106 potential targets were detected, and the high-affinity targets, namely Keap1 and SIRT1, were located through the PPI network. The results of GO and KEGG analysis indicated that the reaction to oxidative stress and BAs homeostasis are significantly associated with the RDP treatment of CLI. In the in vivo experimental study, the findings revealed that RDP alleviated the BDL-induced oxidative damage. Simultaneously, RDP augmented the expressions of BAs efflux transporters and the metabolic enzymes in liver tissues, thus promoting BAs excretion and metabolism in cholestatic rodents. Mechanically, RDP attenuated hepatic oxidative stress and the accumulation of BAs, protecting the liver from BDL-induced cholestasis via the Keap1/Nrf2 and SIRT1/FXR signaling axis. The molecular docking result indicated that bolusanthol C and 3,6,3',4'-tetrahydroxyflavone possess a superior binding affinity to the two core targets (Keap1, SIRT1).

Conclusion: These results suggest that RDP ameliorate CLI by regulating BAs homeostasis and alleviating oxidative stress through the SIRT1/FXR and Keap1/Nrf2 signaling pathways, presenting a novel therapeutic strategy for cholestasis. Additionally, bolusanthol C and 3,6,3',4'-tetrahydroxyflavone may function as key pharmacological agents in RDP, responsible for its protective effects against CLI.

Keywords: Antioxidant; Bile acid homeostasis; Cholestatic liver injury; Keap1/Nrf2; Ribes diacanthum Pall; SIRT1/FXR.