Volume 10 Number 1 2026
RNA Modifications Reprogram the Epitranscriptome to Drive Hepatocellular Carcinoma Progression
Moazzam Hossian 1, Md. Mahmudul Hasan 2, Afrin Sultana 3, Shib Shankar Das 4, Pravas Paul 5, Md Shamsuzzaman 6, Md Samiul Bashir 7*
Integrative Biomedical Research 10 (1) 1-8 https://doi.org/10.25163/biomedical.10110924
Submitted: 26 May 2026 Revised: 12 July 2026 Accepted: 22 July 2026 Published: 24 July 2026
Hepatocellular carcinoma (HCC) remains among the deadliest solid tumors worldwide, and despite decades of genomic profiling, much of its clinical unpredictability cannot be explained by DNA mutations alone. Attention has increasingly turned to a regulatory layer downstream of the genome — chemical marks written onto RNA, collectively termed the epitranscriptome. This review addresses how RNA modifications, principally N6-methyladenosine (m6A), 5-methylcytosine (m5C), and N7-methylguanosine (m7G), shape liver cancer biology and whether this knowledge can be translated clinically. We performed a structured narrative synthesis of peer-reviewed literature in PubMed and related databases, screening studies characterizing epitranscriptomic writers, erasers, and readers in human HCC tissue, cell lines, and patient data, cross-referenced against work on DNA methylation, histone modification, non-coding RNA biology, and mesenchymal stem cell (MSC)-based delivery platforms. The synthesis reveals a coherent, though incomplete, picture. METTL3-mediated m6A silences tumor suppressors such as SOCS2 while promoting invasive CD44 splice variants, partly counterbalanced by the tumor-suppressive isoform METTL3-D. NSUN2-driven m5C stabilizes lncRNA H19 and suppresses interferon signaling, while METTL1/WDR4-mediated m7G enhances oncogenic transcript translation via lncRNA NRAV. These pathways intersect with DNA hypermethylation (DNMT1), repressive histone marks (EZH2/H3K27me3), and histone lactylation (H3K18la), forming a multi-layered circuit varying by disease etiology. MSC- and exosome-based carriers show early promise for targeted delivery of epitranscriptome-modulating agents. Collectively, evidence positions RNA modifications as a central, targetable axis of hepatocarcinogenesis, requiring standardized, single-nucleotide-resolution detection and etiology-stratified validation before clinical translation.
Keywords: hepatocellular carcinoma; epitranscriptome; N6-methyladenosine; METTL3; 5-methylcytosine; N7-methylguanosine; RNA-binding proteins
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