Human endogenous retrovirus ERVK3-1 characterizes a metabolically active and immunosuppressive subtype of liver cancer.

BACKGROUND: Human endogenous retroviruses (HERVs), particularly the HERV-K family, are increasingly recognized for their roles in cancer biology, yet the function of ERVK3-1 (HERVK_3p21.31) in liver hepatocellular carcinoma (LIHC) remains largely unexplored. METHODS: We analyzed transcriptomic data from the TCGA-LIHC cohort to identify differentially expressed genes (DEGs) between high and low ERVK3-1 expression groups, followed by functional enrichment analyses (GO, KEGG, GSEA), protein-protein interaction (PPI) network construction, and hub gene identification. The immunological relevance of ERVK3-1 was assessed through TIP immune cycle analysis, single-cell RNA sequencing datasets, and correlation with immune checkpoint expression. Immunotherapy responsiveness was evaluated using TIDE and TCIA databases. RESULTS: High ERVK3-1 expression was associated with enrichment in metabolic and oxidative stress-related pathways, while low expression correlated with cell cycle and DNA replication. PPI analysis revealed mitosis-related hub genes (e.g., CCNB1, CDK1). ERVK3-1 expression promoted early immune cell recruitment but was inversely correlated with later stages of the cancer immunity cycle, including immune infiltration and T-cell killing. Single-cell data showed high ERVK3-1 expression in immunosuppressive subsets, alongside positive associations with inhibitory immune checkpoints (e.g., PD-1, CTLA-4, TIM-3). High ERVK3-1 expression also correlated with greater immune evasion and reduced immunotherapy responsiveness. CONCLUSIONS: ERVK3-1 plays a multifaceted role in LIHC progression, contributing to metabolic reprogramming, immune suppression, and resistance to immunotherapy. These findings highlight ERVK3-1 as a potential prognostic biomarker and therapeutic target in liver cancer.