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

Hepatic stellate cells (HSCs) are essential drivers of fibrogenesis. Inducing activated-HSC apoptosis is a promising strategy for treating hepatic fibrosis. 18beta-glycyrrhetinic acid (18 beta-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 18 beta-GA decreased hepatic fibrosis by inducing the apoptosis in activated HSCs. 18 beta-GA inhibited the expression of alpha-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 18 beta-GA covalently targeted peroxiredoxin 1 (PRDX1) and peroxiredoxin 2 (PRDX2) proteins via binding to active cysteine residues and thereby inhibited their enzymatic activities. 18 beta-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 18 beta-GA in ameliorating hepatic fibrosis, highlighting the future development of 18 beta-GA as a novel therapeutic drug for hepatic fibrosis. (C) 2022 The Author(s). Published by Elsevier B.V. on behalf of Xi'an Jiaotong University

Automated summary

18beta-glycyrrhetinic acid (18 beta-GA) decreases hepatic fibrosis by inducing the apoptosis of activated hepatic stellate cells (HSCs). It targets peroxiredoxin proteins (PRDX1 and PRDX2) by binding to active cysteine residues, inhibiting their enzymatic activities. This leads to an increase in reactive oxygen species (ROS) and subsequent apoptosis of activated HSCs. The study highlights the potential of 18 beta-GA as a novel therapeutic drug for hepatic fibrosis.