An integrative omics-guided druggability analysis of VCX2 in hepatocellular carcinoma using Peruvian natural products.

Introduction: Hepatocellular carcinoma (HCC) is among the deadliest cancers, and current biomarkers offer limited diagnostic and therapeutic utility. Identifying novel druggable targets remains a critical challenge for improving HCC management. Methods: We implemented an omics-guided computational pipeline integrating single-cell RNA sequencing (scRNA-seq), differential gene expression (DGE) analysis, UMAP clustering, and protein-protein interaction (PPI) network mapping to prioritize candidate genes. Structural characterization of the selected target was performed using AlphaFold-derived models followed by long-timescale molecular dynamics (MD) simulations. Virtual screening of the PeruNPDB (Peruvian Natural Products Database) was conducted using Glide docking, with further evaluation by MM-GBSA and MD-based interaction analyses. Results: Among prioritized genes (TMBIM4, RGS5, CEACAM7, and VCX2), the cancer/testis antigen VCX2 emerged as a promising candidate due to its aberrant expression and potential involvement in chromosomal instability. MD refinement yielded a stable and ligand-accessible VCX2 conformation. Virtual screening identified luteolin-5-O-glucoside from Discussion: These findings support VCX2 as a potential molecular target in HCC and highlight luteolin-5-O-glucoside as a promising lead scaffold. This study provides a hypothesis-generating framework that integrates single-cell transcriptomics with structure-based druggability analysis, offering new avenues for targeted therapeutic development in HCC.