Journal Article

18beta-glycyrrhetinic acid induces ROS-mediated apoptosis to ameliorate hepatic fibrosis by targeting PRDX1/2 in activated HSCs

Guo, Qiuyan, Wong, Yin Kwan, Zhang, Qian, Zheng, Liuhai, He, Xueling, Luo, Piao, Chen, Jiayun, Gu, Liwei, Tang, Huan, Yang, Chuanbin, Xia, Fei, Li, Jiahao, Zhang, Junzhe, Liu, Dandan, Shi, Qiaoli, Wang, Jigang

2022

Overview

Hepatic stellate cells (HSCs) are essential drivers of fibrogenesis. Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis. 18beta-glycyrrhetinic acid (18β-GA) is a natural compound that exists widely in herbal medicines, such as Glycyrrhiza uralensis Fisch, which is used for treating multiple liver diseases, especially in Asia. In the present study, we demonstrated that 18β-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs. 18β-GA inhibited the expression of α-smooth muscle actin and collagen type I alpha-1. Using a chemoproteomic approach derived from activity-based protein profiling, together with cellular thermal shift assay and surface plasmon resonance, we found that 18β-GA covalently targeted peroxiredoxin 1 (PRDX1) and peroxiredoxin 2 (PRDX2) proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities. 18β-GA induced the elevation of reactive oxygen species (ROS), resulting in the apoptosis of activated HSCs. PRDX1 knockdown also led to ROS-mediated apoptosis in activated HSCs. Collectively, our findings revealed the target proteins and molecular mechanisms of 18β-GA in ameliorating hepatic fibrosis, highlighting the future development of 18β-GA as a novel therapeutic drug for hepatic fibrosis. [Display omitted] •18β-GA ameliorates hepatic fibrosis and inhibits ECM deposition.•18β-GA directly targets PRDX1 and PRDX2 in activated HSCs.•18β-GA binding to the cysteines of PRDX1 and PRDX2 inhibits their enzyme activities.•18β-GA induces ROS-mediated activated-HSC apoptosis by targeting PRDX1 and PRDX2.

• Publisher: Elsevier B.V,Xi'an Jiaotong University, Journal of Pharmaceutical Analysis,Artemisinin Research Center and Institute of Chinese Materia Medica,Chinese Academy of Chinese Medical Sciences,Beijing,100700,China,Department of Geriatrics,Shenzhen People's Hospital(The Second Clinical Medical College,Jinan University),Shenzhen,518020,China%Department of Geriatrics,Shenzhen People's Hospital(The Second Clinical Medical College,Jinan University),Shenzhen,518020,China%Artemisinin Research Center and Institute of Chinese Materia Medica,Chinese Academy of Chinese Medical Sciences,Beijing,100700,China%Department of Biological Sciences,National University of Singapore,Singapore,117543,Singapore,Xi'an Jiaotong University
• Subject: Acids / Actin / Apoptosis / Chromatography / Collagen / Collagen (type I) / Enzymatic activity / Fibrosis / Flow cytometry / Glycyrrhetinic acid / Hepatic fibrosis / Hepatitis / Herbal medicine / Laboratory animals / Liver / Liver diseases / Metabolism / Metabolites / Molecular modelling / Original / Pathogenesis / Peroxiredoxin / Proteins / Reactive oxygen species / Smooth muscle / Stellate cells / Surface plasmon resonance