Exploring the antitumor potential of cucurbitacin B in hepatocellular carcinoma through network pharmacology, molecular docking, and molecular dynamics simulations

Abstract

Cucurbitacin B exhibits promising anticancer activity across various cancers; however, its precise mechanism remains unclear. This study integrates network pharmacology, molecular docking, and dynamics simulations to elucidate CuB's multitarget therapeutic mechanisms against HCC. Potential CuB targets were retrieved from CTD, HERB, SwissTargetPrediction, ETCM, and PharmMapper databases. HCC-related genes were sourced from GEO datasets (GSE216613, GSE101685, GSE62232, GSE46408), GeneCard, DisGeNET, OMIM, and TTD. Intersecting targets were analyzed via PPI networks (STRING/Cytoscape), followed by GO/KEGG enrichment (DAVID). Molecular docking (Autodock Vina), ADMET evaluation (ADMETlab 2.0), and molecular dynamics simulations (Amber20) validated interactions. Core targets were further verified using GEPIA, HPA, cBioPortal, and TIMER databases. A total of 139 shared targets were identified between CuB and HCC. Key targets included EGFR, MTOR, MMP9, HSP90AB1, STAT3, and TNF. KEGG pathway analysis revealed significant enrichment in the phosphatidylinositol 3-kinase/protein kinase B (PI3K-Akt) signaling pathway, alongside cancer-related pathways (e.g., lipid metabolism, EGFR tyrosine kinase inhibitor resistance). Molecular docking confirmed strong binding (energy < - 5.0 kcal/mol) between CuB and core targets (e.g., MTOR: - 8.2 kcal/mol; HSP90AB1: - 7.9 kcal/mol). ADMET profiling indicated favorable pharmacokinetic properties, and molecular dynamics simulations demonstrated stable ligand-receptor complexes (RMSD < 2.5 Å). External validation highlighted differential expression (HSP90AB1, TNF) and clinical correlations (CCND1, EGFR) in HCC. CuB exerts antitumor effects in HCC through multitarget modulation, primarily via PI3K-Akt signaling and interactions with EGFR, MTOR, and HSP90AB1. This study provides a mechanistic foundation for CuB's therapeutic potential in HCC, guiding future experimental and clinical investigations.

Keywords: Cucurbitacin B; Hepatocellular carcinoma; Molecular docking; Molecular dynamics; Molecular mechanism; Network pharmacology.