Systems-level transcriptomic analysis reveals hub genes and therapeutic targets of Hepatitis C virus core protein in hepatocytes

Chronic Hepatitis C virus (HCV) disease is an important causative factor for hepatocellular carcinoma (HCC) but remains a challenge even after direct-acting antiviral (DAA) induced viral eradication. Its underlying molecular mechanisms, more specifically the contribution of the HCV core protein, remain poorly defined. This study provides a systems-level characterization of transcriptional alterations associated with HCV core protein expression, addressing a significant knowledge gap in the field. Transcriptomic data (GSE2067) from HepG2 hepatocytes transfected with the HCV core protein were analyzed using GEO2R for differential expression. Overexpressed genes were integrated into a protein–protein interaction network to find important genes via CytoHubba. Functional enrichment analyses were conducted to elucidate functional alterations. Using UALCAN, we confirmed hub gene expression and prognostic significance in TCGA liver cancer datasets. DrugBank was used to study drug-gene interactions, and molecular docking was used to find drugs that could be used again to target key hub proteins. Our study identified 132 differentially expressed genes, with six hub genes (SOX9, DLK1, RXRA, FOLR1, MATN3, and INS-IGF2) identified as central nodes in the PPI network associated with HCV core protein expression. Enrichment studies revealed dysregulation of developmental pathways, nuclear receptor signaling, intracellular trafficking, and lipid metabolism remodeling, indicative of a dedifferentiation-associated transcriptional signature and carcinogenic remodeling favoring metabolism. TCGA-LIHC validation showed significantly higher expression of SOX9, MATN3 and RXRA in primary HCC tissues than in normal liver tissues, whereas FOLR1, DLK1 and INS-IGF2 showed significantly lower expression. RXRA and FOLR1 were identified as druggable targets, with molecular docking predicting favorable interactions with the FDA-approved drugs bexarotene and methotrexate, respectively. These compounds represent candidate agents warranting further experimental investigation. Our study provides a systems-level analysis of gene network alterations associated with HCV core protein expression in HepG2 cells. These findings highlight the potential biological relevance of the identified hub genes in HCV core protein-associated transcriptional alterations and HCC-related pathways. The drug-target predictions provide testable hypotheses for future experimental investigation rather than evidence of therapeutic efficacy.