Locus-Specific Endogenous Retroviral Transcriptional Modulation in Viral Hepatitis-Driven Hepatocellular Carcinoma

Human endogenous retroviruses (HERVs) are remnants of ancient infections integrated into the primate germ line. HERV transcriptional reactivation has been observed in several diseases, including cancer, where it may reflect epigenetic deregulation, cellular stress, inflammation, and infections. Hepatocellular Carcinoma (HCC) is one of the most diffuse and deadly cancers worldwide, with chronic hepatitis infections as major etiological factors. In this context, the activation of specific HERV loci in HCC and their relationship with the broader tumor-associated transcriptional landscape remain poorly defined. Here, we characterized the expression of ∼3,300 HERVs in a public RNA-seq dataset comprising HCC samples, predominantly of viral etiology, and non-HCC liver controls. We identified 185 differentially expressed HERVs, predominantly upregulated in HCC (n=145): comparisons with GTEx healthy liver transcriptomes, inflammatory gene profiling, and covariate-adjusted analyses supported the consistency of this HCC-associated transcriptional signature. Aggregate expression scores of upregulated and downregulated HERVs showed significant associations with histological grade, with opposite trends across G1-G3 tumors. 16 HERV loci were consistently upregulated in all tumor tissues, and their aggregate expression increased significantly with histological grade, supporting their prioritization as a candidate HCC-associated signature. HERV-correlated pathway analyses revealed grade-associated patterns involving metabolic, inflammatory, interferon-related, and proliferative transcriptional programs. De novo transcript reconstruction identified candidate HERV-derived transcripts requiring experimental validation. Overall, the study provides a comprehensive characterization of HERV modulation in a predominantly viral-associated HCC cohort and identifies conserved HERV signatures embedded within the broader transcriptomic remodeling, for future independent and functional studies of their potential relevance to liver cancer biology.