Integrative Computational Analysis of VCX2 in Hepatocellular Carcinoma: From Potential Biomarker Discovery to Therapeutic Targeting with Peruvian Natural Products

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality, often developing in the context of chronic liver disease, fibrosis, and cirrhosis. Identifying novel biomarkers with diagnostic and therapeutic potential is essential, particularly those relevant across multiple cancer types. This study integrates single-cell RNA sequencing (scRNA-seq) data from healthy and diseased liver tissues, analyzing different cellular lineages to identify genes involved in fibrosis, angiogenesis, immune modulation, and apoptosis regulation. Uniform Manifold Approximation and Projection (UMAP) clustering, differential gene expression (DEG) analysis, and protein-protein interaction (PPI) network construction were employed to identify genes contributing to tumor progression and metabolic reprogramming. Key genes, including Transmembrane BAX Inhibitor Motif Containing 4 (TMBIM4), Regulator of G-protein signaling 5 (RGS5), CEA Cell Adhesion Molecule 7 (CEACAM7), and Variable Charge X-Linked 2 (VCX2), exhibited significant roles in tumorigenesis and chromosomal stability. VCX2, a cancer/testis antigen, emerged as a potential biomarker and druggable target due to its altered expression among multiple cancers. Structural modeling and molecular docking (MD) of VCX2 identified a high affinity binding pocket, guiding a virtual screening of Peruvian natural products. Luteolin-5-O-glucoside, from Equisetum arvense, was identified as the most promising compound, showing a strong docking score (-7.42 kcal/mol) and favorable binding free energy ({Delta}G_bind = -40.13 kcal/mol). MMGBSA calculations revealed stabilizing hydrogen bonds with PRO91, GLU97, and GLU109, reinforcing its strong binding stability. These findings position VCX2 as a promising target for HCC therapy and suggest Luteolin-5-O-glucoside as a lead compound with high drug-like potential. Further studies should focus on experimental validation, molecular dynamics simulations, and structure-activity relationship (SAR) optimization to advance VCX2-targeted therapies. Highlight statementsO_LIVCX2 as a Biomarker exhibited differential expressions in HCC versus healthy liver tissue and a suggested role in tumor progression and chromosomal stability. C_LIO_LILuteolin-5-O-glucoside from Equisetum arvense was identified as a promising compound: strong docking score (-7.42 kcal/mol), favorable binding free energy ({Delta}G_bind = -40.13 kcal/mol), and stabilized interactions with key amino acids (PRO91, GLU97, GLU109). C_LIO_LIVCX2 may serve as an oncogenic driver; small molecule inhibition could desensitize tumor cells that need further refinement and validation of structural models due to lack of experimentally resolved crystal structure. C_LIO_LIVCX2 is a novel biomarker and drug target for HCC with Luteolin-5-O-glucoside presents potential for targeted therapy, paving the way for precision medicine approaches. C_LI