EHMT2 and INMT as Methyltransferase Related Biomarkers Predicting Prognosis in HBV Associated Hepatocellular Carcinoma

Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains a major global health challenge, yet the molecular mechanisms linking antiviral therapy to hepatocarcinogenesis are not fully elucidated. In this study, we systematically analyzed transcriptomic data from TCGA and GEO to identify methyltransferase-related prognostic biomarkers in HBV-HCC. Twenty-six differentially expressed methyltransferase genes were identified, among which EHMT2 and INMT emerged as key prognostic factors. A two-gene risk model based on these markers effectively stratified patients into high- and low-risk groups, demonstrating robust predictive performance independent of conventional clinical variables. Functional enrichment and immune profiling revealed that high-risk patients exhibited cell cycle activation, DNA repair pathway enrichment, and reduced immune infiltration, whereas low-risk patients showed enhanced immune responses and Wnt signaling activity. In vitro experiments further demonstrated that tenofovir disoproxil fumarate (TDF) treatment of HepAD38 cells suppressed HBV replication, downregulated EHMT2, upregulated INMT, and globally reduced DNA methylation, indicating that antiviral therapy may modulate the epigenetic landscape to impede HCC progression. Collectively, our findings establish an EHMT2–INMT-based prognostic model, provide mechanistic insights into the interplay between antiviral therapy and epigenetic regulation, and offer a framework for personalized risk assessment and potential therapeutic intervention in HBV-HCC