Glycyrrhizic acid ameliorates hepatic fibrosis by inhibiting oxidative stress via AKR7A2

Wang, Qixin1,2; Lu, Tianming1,2; Song, Ping3; Dong, Yanqi4; Dai, Chuanhao1,2; Zhang, Wenjing5; Jia, Xuan1,2; Guo, Zuchang1,2; Zhao, Minghong1,2; Zhang, Junzhe1,2; Wang, Peili3; Wang, Jigang1,2,6,7; Guo, Qiuyan1,2

2024-10-01

10.1016/j.phymed.2024.155878

PHYTOMEDICINE   影响因子和分区

0944-7113

1618-095X

Background: Hepatic fibrosis is a reversible pathological phenomenon caused by the abnormal proliferation of connective tissues in the liver for self-repair after persistent liver injury. Among these tissues, the activation status of hepatic stellate cells (HSCs) is crucial. Glycyrrhizic acid (GA) agents have been proven to have excellent anti-fibrosis effects, but their targets are unclear. Purpose: To investigate the anti-hepatic fibrosis effect of GA and its target in activated HSCs. Methods: A mouse model of hepatic fibrosis was prepared with 20 % carbon tetrachloride (CCl4) and GA was administered continuously for 4 weeks. Subsequently, the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), type III procollagen peptide (P III P), laminin (LN), hyaluronic acid (HA), and type IV collagen (Col IV) were measured. Liver tissues were subjected to hematoxylin and eosin (HE), Masson, and Sirius red staining and proteome sequencing analysis. Based on LX-2 cells, activity-based protein profiling (ABPP) was used to investigate the potential targets of GA, which was further validated by the cellular thermal shift assay (CETSA), immunofluorescence co-localization, molecular docking, small interfering RNA (siRNA) and western blot (WB) assays. Results: In vivo, GA significantly reduced serum ALT, AST, HA, P III P, Col IV, and LN levels. HE, Masson, and Sirius red staining showed that GA significantly ameliorated hepatic inflammatory response and collagen deposition in CCl4-treated mice. Proteome sequencing results showed that GA mainly regulated glutathione Stransferase family members involved in glutathione metabolism. In vitro, GA significantly inhibited LX-2 cell proliferation and reduced reactive oxygen species accumulation. ABPP suggested that aldo-keto reductase family 7 member A2 (AKR7A2) was the major binding protein of GA in LX-2 cells. CETSA, fluorescence co-localization, molecular docking , surface plasmon resonance further validated GA binding to AKR7A2. The WB results showed that GA up-regulated AKR7A2 expression both in vitro , in vivo and was corroborated by siRNA experiments. Conclusion: GA targeted AKR7A2 in LX-2 cells to defend against sustained oxidative stress injury, thereby inhibiting the proliferation of activated HSCs and reversing hepatic fibrosis.

Glycyrrhizic acid Hepatic fibrosis Activity-based protein profiling

SCI

英语

通讯

National Natural Science Foundation of China["82104480","82004248"] ; Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine[ZYYCXTD-C-202002] ; Young Elite Scientists Sponsorship Program by CACM[2021QNRC2B29] ; Young Elite Scientists Sponsorship Program by BAST["BYESS2024269","ZZ14-YQ-055","ZXKT19021","ZZ14-YQ-059","ZXKT19022","ZZ14-YQ-060","ZZ16-ND-10-05","ZZ16-ND-10-17","CI2023E002","CI2023E005TS04"] ; Fundamental Research Funds for the Central Public Welfare Research Institutes["ZZ14-YQ-055","ZXKT19021","ZZ14-YQ-059","ZXKT19022","ZZ14-YQ-060","ZZ16-ND-10-05","ZZ16-ND-10-17","CI2023E002","CI2023E005TS04","ZXKT19018"]

Plant Sciences ; Pharmacology & Pharmacy ; Integrative & Complementary Medicine

Plant Sciences ; Chemistry, Medicinal ; Integrative & Complementary Medicine ; Pharmacology & Pharmacy

WOS:001293133500001

ELSEVIER GMBH

PHARMACOLOGY & TOXICOLOGY

Web of Science

1.China Acad Chinese Med Sci, Artemisinin Res Ctr, State Key Lab Qual Ensurance & Sustainable Use Dao, Beijing 100700, Peoples R China
2.China Acad Chinese Med Sci, Inst Chinese Mat Med, Beijing 100700, Peoples R China
3.China Acad Chinese Med Sci, Xiyuan Hosp, 1 Xiyuan Playground, Beijing 100091, Peoples R China
4.Univ Hong Kong, Sch Publ Hlth, Hong Kong 999077, Peoples R China
5.Chinese Med Assoc, Beijing 100710, Peoples R China
6.Jinan Univ, Southern Univ Sci & Technol, Affiliated Hosp 1, Clin Med Coll 2,Shenzhen Peoples Hosp,Guangdong Pr, Shenzhen 518020, Guangdong, Peoples R China
7.Henan Univ, Sch Pharm, State Key Lab Antiviral Drugs, Kaifeng 475004, Peoples R China

Wang, Qixin,Lu, Tianming,Song, Ping,et al. Glycyrrhizic acid ameliorates hepatic fibrosis by inhibiting oxidative stress via AKR7A2[J]. PHYTOMEDICINE,2024,133.

Wang, Qixin.,Lu, Tianming.,Song, Ping.,Dong, Yanqi.,Dai, Chuanhao.,...&Guo, Qiuyan.(2024).Glycyrrhizic acid ameliorates hepatic fibrosis by inhibiting oxidative stress via AKR7A2.PHYTOMEDICINE,133.

Wang, Qixin,et al."Glycyrrhizic acid ameliorates hepatic fibrosis by inhibiting oxidative stress via AKR7A2".PHYTOMEDICINE 133(2024).