Proteomic and Transcriptomic Analyses Define Molecular Subtypes, Identify Biomarkers, and Suggest Potential Therapeutic Agent for Early-Stage HBV-Related Hepatocellular Carcinoma

Molecular heterogeneity in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) complicates patient stratification. Here, we perform integrative proteomic analysis on 272 early stage HBV-HCC tumors from four East Asian cohorts, uncovering two robust molecular subtypes. Group B (<i>n</i> = 53) is associated with hyperproliferation, oncogenic signaling, and significantly poorer overall (<i>P</i> <0.001) and relapse-free survival (<i>P</i> <0.05). In contrast, group A (<i>n</i> = 219) is enriched in differentiation and metabolic pathways. These findings are validated by matched transcriptomics (<i>n</i> = 108), aligning with established classifications. We identify subtype-specific protein signatures, with CD46, HNF1A, and ATP1B1 exclusively expressed in the aggressive group B. Finally, computational drug sensitivity prediction, validated by molecular docking, nominates Sunitinib as a potential therapy for group B patients. Our work provides a proteomic framework for improved prognostication and targeted therapy in high-risk HBV-HCC.