基于网络药理学和分子对接探讨中药调控铁死亡干预抗结核药物性肝损伤的成分筛选及作用机制  

Exploration of Ingredients Screening and Mechanism of Chinese Medicinals Regulating Ferroptosis for Intervening Anti-Tuberculosis Drug-Induced Liver Injury Based on the Network Pharmacology and Molecular Docking

作　　者：周阿益 金立君 邵深深 陈瑶如 ZHOU A'yi;JIN Lijun;SHAO Shenshen;CHEN Yaoru(Department of Pharmacy,Wenzhou People's Hospital,Wenzhou Zhejiang 325000,China)

机构地区：[1]温州市人民医院药剂科,浙江温州325000

出　　处：《新中医》2025年第5期179-186,共8页New Chinese Medicine

摘　　要：目的:利用网络药理学和分子对接分析识别抗结核药物诱导的药物性肝损伤与铁死亡相关的关键基因,并预测相关作用的中药及有效成分。方法:利用PubChem、Swiss Target Prediction平台获得抗结核药物的药物靶点;基于Gene Cards数据库收集药物性肝损伤的疾病靶点,取“疾病-药物”交集靶点,运用Cytoscape软件构建蛋白相互作用网络关系图,结合CytoHubba插件获得核心靶点。应用DAVID数据库进行基因本体功能(GO)富集和京都基因与基因组百科全书(KEGG)通路分析。通过FerrDb数据库筛选出铁死亡相关的关键基因,利用HERB数据库、TCMSP数据库和对关键基因进行中药及有效成分预测,结合Lipinski五倍率法则和ADMETlab 2.0对有效成分进行成药性及人肝毒性筛选,最后筛选出的有效成分进行分子对接。结果:得到抗结核药物与药物性肝损伤共同作用靶点14个,构建蛋白相互作用网络筛选出GPT、CYP2E1、CYP1A2、NR1H4、ABCB11、SLC10A1、CYP7A1、ABCC2、HIF1A和CASP3等关键靶点。通过FerrDb数据库筛选关键基因HIF1A,以HIF1A为靶点筛选并经筛除后得到具有成药性且无人肝毒性的有效成分血根碱、黄芩甙元和槲皮素,且这3种成分与HIF1A均能稳定结合。结论:血根碱、黄芩甙元和槲皮素可能通过调控HIF1A的表达,影响肝脏细胞的铁死亡达到治疗抗结核药物诱导的药物性肝损伤作用。Objective:To analyze and identify the key genes related to ferroptosis in anti-tuberculosis druginduced liver injury by using network pharmacology and molecular docking,and to predict the related Chinese medicinals and active ingredients.Methods:The drug targets of anti-tuberculosis drugs were obtained by platforms of PubChem and Swiss Target Prediction;the disease targets of drug-induced liver injury were collected based on the Gene Cards database,and the“disease-drug”intersection targets were taken.The protein-protein interaction network was established by Cytoscape software,and the core targets were obtained by combining the CytoHubba plug-in.Gene Ontology(GO)function enrichment analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway analysis were performed using the DAVID database.The key genes related to ferroptosis were screened by FerrDb database.The HERB database,TCMSP database and the key genes were used for the prediction of Chinese medicinals and effective ingredients.The effective ingredients were screened for druggability and human hepatotoxicity based on Lipinski's rule of five and ADMETlab 2.0 and the finally selected effective ingredients were subjected to molecular docking.Results:A total of 14 common targets of anti-tuberculosis drugs and drug-induced liver injury were obtained.The established protein-protein interaction network screened out key targets such as GPT,CYP2E1,CYP1A2,NR1H4,ABCB11,SLC10A1,CYP7A1,ABCC2,HIF1A and CASP3.The key gene HIF1A was screened by FerrDb database,and the effective ingredients of sanguinarine,baicalein and quercetin with druggability and no hepatotoxicity were obtained after screening with HIF1A as the target.Conclusion:Sanguinarine,baicalein and quercetin may affect the ferroptosis of liver cells by regulating the expression of HIF1A to achieve the treatment of drug-induced liver injury induced by antituberculosis drugs.

关 键 词：药物性肝损伤 抗结核药物 铁死亡 中药 网络药理学 分子对接 

分 类 号：R249[医药卫生—中医临床基础]