Luteolin-7-diglucuronide,a novel PTP1B inhibitor,ameliorates hepatic stellate cell activation and liver fibrosis in mice  

作　　者：Bi-xi Tang Yong Zhang Dan-dan Sun Qin-yi Liu Cong Li Pei-pei Wang Li-xin Gao Xue-mei Zhang Jia Li Wei-liang Zhu Yi Zang 

机构地区：[1]Department of Pharmacology,School of Pharmacy,Fudan University,Shanghai 21203,China [2]Stake Key Laboratory of Chemical Biology,Shanghai Institute of Materia Medica Chinese Academy of Sciences,Shanghai 201203,China [3]University of Chinese Academy of Sciences,100049 Bejing,China [4]Shandong Laboratory of Yantai Drug Discovery,Bohai Rim Advanced Research Institute for Drug Discovery,Yantai 264117,China [5]Lingang Laboratory,Shanghai 201203,China

出　　处：《Acta Pharmacologica Sinica》2025年第1期122-133,共12页中国药理学报(英文版)

基　　金：This article was supported by Shanghai lnstitute of Materia Medica,Chinese Academy of Sciences(No.CASIMM0120225006-2,SIMM0120232001);Shanghai Municipal Science and Technology Major Project(TM202301H002);Shanghai Committee of Science and Technology(22ZR1415200).

摘　　要：Liver fibrosis,one of the leading causes of morbidity and mortality worldwide,lacks effective therapy.The activation of hepatic stellate cells(HSCs)is the dominant event in hepatic fibrogenesis.Luteolin-7-diglucuronide(L7DG)is the major flavonoid extracted from Perilla frutescens and Verbena officinalis.Their beneficial effects in the treatment of liver diseases were well documented.In this study we investigated the anti-fibrotic activities of L7DG and the potential mechanisms.We established TGF-β1-activated mouse primary hepatic stellate cells(pHSCs)and human HSC line LX-2 as in vitro liver fibrosis models.Co-treatment with L7DG(5,20,50μM)dose-dependently decreased TGF-β1-induced expression of fibrotic markers collagen 1,α-SMA and fibronectin.In liver fibrosis mouse models induced by CCl_(4) challenge alone or in combination with HFHC diet,administration of L7DG(40,150 mg-kg^(-1).d^(-1),i.g.,for 4 or 8 weeks)dose-dependently attenuated hepatic histopathological injury and collagen accumulation,decreased expression of fibrogenic genes.By conducting target prediction,molecular docking and enzyme activity detection,we identifed L7DG as a potent inhibitor of protein tyrosine phosphatase 1B(PTP1B)with an IC_(50) value of 2.10μM.Further studies revealed that L7DG inhibited PTP1B activity,up-regulated AMPK phosphorylation and subsequently inhibited HSC activation.This study demonstrates that the phytochemical L7DG may be a potential therapeutic candidate for the treatment of liver fibrosis.

关 键 词：liver fibrosis PHYTOCHEMICAL luteolin 7-diglucuronide HSC activation PTP1B 

分 类 号：R57[医药卫生—消化系统]