Multilevel data integration and molecular docking approach to systematically elucidate the underlying pharmacological mechanisms of Er-Zhi-Wan against hepatocellular carcinoma

As a multicomponent, multitarget empirical therapy, traditional Chinese medicine (TCM) has been used clinically in Asia for thousands of years. Due to this unique feature, TCM therapy is considered a promising therapeutic strategy for the treatment of hepatocellular carcinoma (HCC). Er-Zhi-Wan (EZW), a well-known TCM formula containing two herbs, Fructus Ligustri Lucidi (FLL, Nü-Zhen-Zi) and Ecliptae Herba (EH, Mo-Han-Lian), is commonly used in clinical practice to prevent and treat liver diseases. Modern pharmacological studies have shown that both EH and FLL can inhibit HCC proliferation. However, the pharmacological mechanism, potential targets, and clinical value of EZW in inhibiting HCC have not been fully elucidated. We used multilevel databases (Gene Expression Omnibus (GEO), Traditional Chinese Medicine Systems Pharmacology (TCMSP), High-throughput Experiment- and Reference-guided database (HERB), and SwissTargetPrediction) to show that EZW suppresses HCC through 19 active components acting on 66 potential targets. Enrichment analysis revealed that EZW mainly regulates HCC progression through various metabolic pathways, the cell cycle, and cellular senescence. Furthermore, we used The Cancer Genome Atlas (TCGA)-LIHC database to analyze the expression patterns and clinical characteristics of cellular senescence-related genes and identified CDK1, CDK4, CHEK1, and G6PD as key therapeutic molecular targets in EZW-suppressed HCC. Molecular docking revealed that EZW could exert its anti-HCC effect by binding various active components to the above cellular senescence-related genes and regulating their activities. In conclusion, we systematically revealed the potential pharmacological mechanisms and molecular targets of EZW against HCC based on multilevel data integration and a molecular docking strategy.