Hepatocellular carcinoma (HCC) is a major global health burden and a leading cause of cancer-related mortality, commonly arising in the setting of cirrhosis and chronic liver disease. Hepatocarcinogenesis is driven by complex genetic and epigenetic alterations, including mutations in tumour protein p53, telomerase reverse transcriptase (TERT), and catenin beta 1, as well as dysregulation of microRNAs and long non-coding RNAs (lncRNAs). These molecular changes have been identified as potential diagnostic and prognostic indicators for HCC. Among telomere-related molecules, telomeric repeat-containing RNA (TERRA), an lncRNA involved in telomere regulation and genomic stability, has emerged as a promising biomarker. However, TERRA represents only one component of the broader molecular network involved in HCC development and progression.
A comprehensive literature search of PubMed, Scopus, Web of Science, and Google Scholar was conducted to identify experimental and clinical studies published between 2010 and 2025 investigating genetic, epigenetic, and circulating molecular markers in HCC patients.
Aim: This systematic review aimed to evaluate current evidence regarding genetic, epigenetic, telomere-related, and circulating molecular biomarkers associated with HCC, emphasizing their diagnostic, prognostic, and disease-monitoring potential.
Available evidence indicates that telomere-related alterations, including dysregulated TERRA expression, are associated with enhanced telomerase activity, telomere length changes, tumor aggressiveness, metastasis, and poor clinical outcomes.
Conclusion: Molecular biomarkers, including TERRA, show promising potential as non-invasive tools for early detection, prognostic stratification, and monitoring of HCC. Further large-scale studies are needed to validate their clinical utility.