Exploring the pharmacological effect of cardiac glycosides against hepatocellular carcinoma using network pharmacology

Abstract

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the third leading cause of cancer-related deaths worldwide. Currently, treatment options for patients with advanced HCC remain limited. Cardiac glycosides (CGs), traditionally used for their cardiac effects, have recently garnered attention for their potential anti-cancer properties. This study aimed to explore the pharmacological effects of CGs against HCC using network pharmacology. Our previous research identified 36 CGs, of which 16 were selected for further analysis based on oral bioavailability, drug-likeness, and toxicity, and were considered active compounds. We retrieved protein targets for these active CGs and HCC-related genes from various databases. The intersection of CGs and HCC-related genes revealed 258 potential therapeutic targets for HCC treatment. The pharmacological mechanisms of CGs were investigated through enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, using the ShinyGO 0.80 bioinformatics platform. GO analysis indicated that the targets of active CGs are involved in key biological processes, such as protein phosphorylation, membrane rafts, protein kinase activity, and ATP binding. Enriched KEGG pathway analysis revealed that the therapeutic effects of CGs against HCC are associated with several critical pathways, including EGFR tyrosine kinase inhibitor resistance, glioma, ErbB signaling, MicroRNAs in cancer, hepatitis B, Rap1 signaling, Kaposi sarcoma-associated herpesvirus infection, focal adhesion, proteoglycans in cancer, MAPK signaling, Ras signaling, and PI3K-Akt signaling. This study utilized network pharmacology to identify potential biomarkers for HCC and lay a foundation for future experimental validation and development of novel anti-HCC drugs using CGs.