Transposable Element Dysregulation in Hepatocellular Carcinoma: Epigenetic Mechanisms, Immune Remodeling, and Translational Opportunities.

Abstract

Hepatocellular carcinoma (HCC) commonly develops in the context of chronic liver injury, viral hepatitis, metabolic dysfunction, alcohol-related liver disease and cirrhosis. Although immune checkpoint inhibitor-based combination therapies have improved the treatment of unresectable HCC, primary and acquired resistance and the lack of reliable predictive biomarkers continue to limit precision treatment. Transposable elements (TEs) and TE-derived sequences represent a regulatory layer linking epigenetic disruption, aberrant transcription and immune remodelling. In HCC, DNA hypomethylation, altered repressive histone modifications, dysfunction of TE-silencing machinery and dysregulated RNA-level control may promote the reactivation of LINE-1, HERV/ERV and other TE-derived sequences. Reactivated TEs may influence tumour-cell states and the immune microenvironment through cryptic promoter or enhancer activity, TE-derived transcripts, viral mimicry, innate immune sensing and potential tumour-associated antigens. HCC-specific evidence includes clinical associations of LINE-1 hypomethylation and mechanistic findings involving the TE/KDM1A/HNF4A axis and SETDB1-mediated HERV/ERV silencing and viral mimicry. Using a structured narrative literature search that emphasised studies published during the past five years while retaining relevant landmark studies, this review integrates the epigenetic, transcriptional, immune and translational dimensions of TE dysregulation in HCC. A five-level evidence framework is applied to distinguish HCC-specific mechanistic and in vivo evidence, HCC functional and cell-based findings, HCC clinical and omics associations, pan-cancer or non-HCC evidence, and hypothesis-generating candidates. This framework highlights the uneven maturity of the field and the need for locus-specific functional studies and independent clinical validation. TIGD family members are discussed as a hypothesis-generating example of TE-derived protein-coding candidates rather than as established HCC regulators, biomarkers or therapeutic targets.