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

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

doi:10.1016/j.jpha.2022.06.001

Volume 12 Issue 4

Sep. 2022

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Article Navigation > Journal of Pharmaceutical Analysis > 2022 > 12(4): 570-582

Qian Zhang, Piao Luo, Liuhai Zheng, Jiayun Chen, Junzhe Zhang, Huan Tang, Dandan Liu, Xueling He, Qiaoli Shi, Liwei Gu, Jiahao Li, Qiuyan Guo, Chuanbin Yang, Yin Kwan Wong, Fei Xia, Jigang Wang. 18beta-glycyrrhetinic acid induces ROS-mediated apoptosis to ameliorate hepatic fibrosis by targeting PRDX1/2 in activated HSCs[J]. Journal of Pharmaceutical Analysis, 2022, 12(4): 570-582. doi: 10.1016/j.jpha.2022.06.001

Citation:

Qian Zhang, Piao Luo, Liuhai Zheng, Jiayun Chen, Junzhe Zhang, Huan Tang, Dandan Liu, Xueling He, Qiaoli Shi, Liwei Gu, Jiahao Li, Qiuyan Guo, Chuanbin Yang, Yin Kwan Wong, Fei Xia, Jigang Wang. 18beta-glycyrrhetinic acid induces ROS-mediated apoptosis to ameliorate hepatic fibrosis by targeting PRDX1/2 in activated HSCs[J]. Journal of Pharmaceutical Analysis, 2022, 12(4): 570-582. doi: 10.1016/j.jpha.2022.06.001

Citation:

Qian Zhang, Piao Luo, Liuhai Zheng, Jiayun Chen, Junzhe Zhang, Huan Tang, Dandan Liu, Xueling He, Qiaoli Shi, Liwei Gu, Jiahao Li, Qiuyan Guo, Chuanbin Yang, Yin Kwan Wong, Fei Xia, Jigang Wang. 18beta-glycyrrhetinic acid induces ROS-mediated apoptosis to ameliorate hepatic fibrosis by targeting PRDX1/2 in activated HSCs[J]. Journal of Pharmaceutical Analysis, 2022, 12(4): 570-582. doi: 10.1016/j.jpha.2022.06.001

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

doi: 10.1016/j.jpha.2022.06.001

a. Artemisinin Research Center and Institute of Chinese Materia Medica, Chinese Academy of Chinese Medical Sciences, Beijing, 100700, China;
b. Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore;
c. Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University), Shenzhen, 518020, China

Funds:

The authors gratefully acknowledge the financial support from the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine, China (Grant No.: ZYYCXTD-C-202002), the National Key Research and Development Program of China, China (Grant No.: 2020YFA0908000), the National Natural Science Foundation of China, China (Grant Nos.: 81803389, 81903588, 32101219, 81702580, 82074098, 81903866, and 81803456), and the Fundamental Research Funds for the Central Public Welfare Research Institutes, China (Grant Nos.: ZZ14-YQ-050, ZZ14-YQ-059, ZZ15-ND-10, ZZ15-YQ-063, ZZ14-ND-010, and ZZ14-FL-002).

Received Date: Dec. 15, 2021
Accepted Date: Jun. 01, 2022
Rev Recd Date: May 31, 2022
Publish Date: Jun. 08, 2022

Abstract

Abstract

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.
- Glycyrrhetinic acid,
- Hepatic fibrosis,
- Peroxiredoxin,
- Reactive oxygen species,
- Apoptosis

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