中药新药与临床药理2026，Vol.37Issue(9)：1620-1628,9.DOI:10.19378/j.issn.1003-9783.2026.09.002
基于Nrf2/HO-1/GPX4通路介导的铁死亡探讨白鲜皮致肝损伤的作用机制
Mechanism of Cortex Dictamni-Induced Liver Injury Based on Ferroptosis Mediated by Nrf2/HO-1/GPX4 Pathway
摘要
Abstract
Objective To investigate the mechanism of liver injury induced by Cortex Dictamni based on ferroptosis mediated by the nuclear factor erythroid 2-related factor 2(Nrf2)/heme oxygenase-1(HO-1)/glutathione peroxidase 4(GPX4)pathway.Methods(1)In vivo experiment:Forty male ICR mice were randomly divided into 4 groups:control group,high-dose Cortex Dictamni group(9.180 g·kg-1),medium-dose Cortex Dictamni group(6.885 g·kg-1),and low-dose Cortex Dictamni group(5.508 g·kg-1).Drugs were administered by gavage(20 mL·kg-1)once daily for 7 consecutive days.Serum levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST),as well as hepatic ferrous ion(Fe2+)and malondialdehyde(MDA)contents,were measured by ELISA.Pathological changes of liver tissue were observed by HE and Prussian blue staining.mRNA and protein expression levels of Nrf2,HO-1,GPX4,GCLM and FPN1 in liver tissue were detected by RT-PCR and Western Blot.(2)In vitro experiment:HepaRG cells were treated with Cortex Dictamni aqueous extract at concentrations of 1,2,4,6,8 and 10 mg·mL-1 for 24 hours,and cell viability was measured by CCK-8 assay to screen the optimal intervention concentrations.HepaRG cells were then divided into control group,high-dose Cortex Dictamni group(8 mg·mL-1),medium-dose group(6 mg·mL-1)and low-dose group(4 mg·mL-1).After 24 hours of intervention,mRNA and protein expression levels of Nrf2,HO-1,GPX4,GCLM and FPN1 were detected by RT-PCR and Western Blot.Results(1)Compared with the control group,serum ALT levels were significantly increased in the medium-and high-dose Cortex Dictamni groups(P＜0.05,P＜0.001),and serum AST levels were significantly elevated in the high-dose group(P＜0.01).Compared with the control group,mice in all Cortex Dictamni groups exhibited marked hepatocyte injury,including cell swelling and rupture,nuclear deformity,severe disruption of cellular structure,disordered hepatic cord arrangement,massive inflammatory cell infiltration,and significantly increased brown iron deposits(P＜0.001).Hepatic Fe2+and MDA levels were significantly elevated(P＜0.05,P＜0.01,P＜0.001),while mRNA and protein expression levels of Nrf2,HO-1,GPX4,GCLM and FPN1 were significantly decreased in liver tissue(P＜0.001).(2)Compared with the control group(0 mg·mL-1),HepaRG cell viability was significantly reduced in all Cortex Dictamni treatment groups(2,4,6,8,10 mg·mL-1)in a dose-dependent manner(P＜0.05,P＜0.001).mRNA and protein expression levels of Nrf2,HO-1,GPX4,GCLM and FPN1 were significantly decreased in all Cortex Dictamni dose groups compared with the control group(P＜0.001).Conclusion Cortex Dictamni aqueous extract can induce liver injury.The underlying mechanism may be related to the inhibition of the Nrf2/HO-1/GPX4 pathway and its downstream target proteins GCLM and FPN1,leading to intracellular iron accumulation and lipid peroxidation,thereby triggering ferroptosis.关键词
白鲜皮/肝损伤/铁死亡/Nrf2/HO-1/GPX4通路/小鼠/HepaRG细胞Key words
Cortex Dictamni/liver injury/ferroptosis/Nrf2/HO-1/GPX4 pathway/mice/HepaRG cells分类
医药卫生引用本文复制引用
贺文杰,孙慧娟,张萌萌,邓戈宇,黄琳,高蕊,卢芳,刘树民..基于Nrf2/HO-1/GPX4通路介导的铁死亡探讨白鲜皮致肝损伤的作用机制[J].中药新药与临床药理,2026,37(9):1620-1628,9.基金项目
国家重点研发计划-中医药现代化项目(2022YFC3502100,2022YFC3502102,2022YFC3502102-04). （2022YFC3502100,2022YFC3502102,2022YFC3502102-04）
