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
Abstract: 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.