Integrative Biomedical Research
Integrative Biomedical Research (Journal of Angiotherapy) | Online ISSN 3068-6326
463
Citations
1.8m
Views
768
Articles
Volume 10 Number 1 2026
REVIEWS (Open Access)
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
Abstract
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
References
Arechederra, M., Recalde, M., Gárate-Rascón, M., Fernández-Barrena, M. G., Ávila, M. A., & Berasain, C. (2021). Epigenetic biomarkers for the diagnosis and treatment of liver disease. Cancers, 13(6), 1265. https://doi.org/10.3390/cancers13061265
Cai, B., Lv, D., Qiu, Q., Xiong, W., Tang, H., Bai, Y., Zhou, S., Hu, Y., Safadi, R., Wang, C., & Zhou, L. (2026). Epigenetic alterations in hepatocellular carcinoma: Mechanisms and biomarkers for precision therapy. Cancers, 18(2), 2224.
Calcat-I-Cervera, S., Rendra, E., Scaccia, E., Amadeo, F., Hanson, V., Wilm, B., Murray, P., O’Brien, T., Taylor, A., & Bieback, K. (2023). Harmonised culture procedures minimize but do not eliminate mesenchymal stromal cell donor and tissue variability in a decentralised multicentre manufacturing approach. Stem Cell Research & Therapy, 14(1), 120. https://doi.org/10.1186/s13287-023-03352-1
Calderon-Cisneros, A., Barrena, M. G. F., & Avila, M. A. (2020). Epigenetic alterations involved in fibrogenic HSCs transdifferentiation with particular focus on histones acetylation changes. Cells, 9(10), 2321.
D’Agnano, I., & Berardi, A. C. (2020). Extracellular vesicles, a possible theranostic platform strategy for hepatocellular carcinoma—An overview. Cancers, 12(2), Article 261.
Du, W., Tan, S., Peng, Y., Lin, S., Wu, Y., Ding, K., Chen, C., Liu, R., Cao, Y., Li, Z., et al. (2024). Histone lactylation-driven YTHDC1 promotes hepatocellular carcinoma progression via lipid metabolism remodeling. Cancer Letters, 611, 217426.
Eun, J. W., Cheong, J. Y., Jeong, J.-Y., & Kim, H. S. (2023). A new understanding of long non-coding RNA in hepatocellular carcinoma—From m6A modification to blood biomarkers. Cells, 12(18), Article 2272.
Gao, Y., Wang, J.-P., Hong, D.-F., Yang, C., & Naranmandura, H. (2025). Mesenchymal stem cell-mediated targeted drug delivery systems for hepatocellular carcinoma: Current advances and future directions. Bioengineering, 12(11), Article 1206.
Han, T. S., Ban, H. S., Hur, K., & Cho, H. S. (2018). The epigenetic regulation of HCC metastasis. International Journal of Molecular Sciences, 19(12), 3978.
Hussain, M. S., Moglad, E., Afzal, M., Gupta, G., Almalki, W. H., Kazmi, I., Alzarea, S. I., Kukreti, N., Gupta, S., Kumar, D., et al. (2024). Non-coding RNA mediated regulation of PI3K/Akt pathway in hepatocellular carcinoma: Therapeutic perspectives. Pathology - Research and Practice, 258, 155303.
Hussain, M. S., Vij, P., Kotnala, S., Ahmad, S., Chauhan, S. C., & Tripathi, M. K. (2025). Approaches for identifying lncRNA-associated proteins for therapeutic targets and cancer biomarker discovery. Targets, 3(1), 27. https://doi.org/10.3390/targets3030027
Kim, H.-R., & Kim, J. (2025). VPS26A as a prognostic biomarker and therapeutic target in liver hepatocellular carcinoma: Insights from comprehensive bioinformatics analysis. Medicina, 61(7), 1283. https://doi.org/10.3390/medicina61071283
Krawczenko, A., & Klimczak, A. (2022). Adipose tissue-derived mesenchymal stem/stromal cells and their contribution to angiogenic processes in tissue regeneration. International Journal of Molecular Sciences, 23(5), 2425.
Lai, S.-Y., Zhu, X.-J., Sun, W.-D., Bi, S.-Z., Zhang, C.-Y., Liu, A., & Li, J.-H. (2025). Nicotinamide N-methyltransferase (NNMT) and liver cancer: From metabolic networks to therapeutic targets. Biomolecules, 15(5), 719. https://doi.org/10.3390/biom15050719
Lanzafame, M., Ng, C. K. Y., & Piscuoglio, S. (2018). Long non-coding RNAs in hepatocellular carcinoma: From biogenesis to clinical significance. International Journal of Molecular Sciences, 19(3), 682.
Li, G., Deng, L., Huang, N., Cui, Z., Wu, Q., Ma, J., Pan, Q., & Sun, F. (2021b). m6A mRNA methylation regulates LKB1 to promote autophagy of hepatoblastoma cells through upregulated phosphorylation of AMPK. Genes, 12(11), 1747. https://doi.org/10.3390/genes12111747
Li, H., Yang, C., Shi, Y., & Zhao, L. (2018). Exosomes derived from siRNA against GRP78 modified bone-marrow-derived mesenchymal stem cells suppress sorafenib resistance in hepatocellular carcinoma. Journal of Nanobiotechnology, 16, Article 103. https://doi.org/10.1186/s12951-018-0429-z
Li, Y., Qi, D., Zhu, B., & Ye, X. (2021a). Analysis of m6A RNA methylation-related genes in liver hepatocellular carcinoma and their correlation with survival. International Journal of Molecular Sciences, 22(3), 1474. https://doi.org/10.3390/ijms22031474
Liu, X., Xie, W., Meng, S., Kang, X., Liu, Y., Guo, L., & Wang, C. (2022). Small nucleolar RNAs and their comprehensive biological functions in hepatocellular carcinoma. Cells, 11(16), 2654.
Lou, G., Chen, L., Xia, C., Wang, W., Qi, J., Li, A., Zhao, L., Chen, Z., Zheng, M., & Liu, Y. (2020). MiR-199a-modified exosomes from adipose tissue-derived mesenchymal stem cells improve hepatocellular carcinoma chemosensitivity through mTOR pathway. Journal of Experimental & Clinical Cancer Research, 39, Article 4. https://doi.org/10.1186/s13046-019-1512-5
Lou, G., Song, X., Yang, F., Wu, S., Wang, J., Chen, Z., & Liu, Y. (2015). Exosomes derived from miR-122-modified adipose tissue-derived MSCs increase chemosensitivity of hepatocellular carcinoma. Journal of Hematology & Oncology, 8, Article 122. https://doi.org/10.1186/s13045-015-0220-7
Ong, H.-T., Federspiel, M. J., Guo, C. M., Ooi, L. L., Russell, S. J., Peng, K.-W., & Hui, K. M. (2013). Systemically delivered measles virus-infected mesenchymal stem cells can evade host immunity to inhibit liver cancer growth. Journal of Hepatology, 59(5), 999–1006. https://doi.org/10.1016/j.jhep.2013.07.010
Patel, A. A., Mohamed, A. H., Rizaev, J., Mallick, A. K., Qasim, M. T., Al Abdulmonem, W., Jamal, A., Hattiwale, H. M., Kamal, M. A., & Ahmad, F. (2024). Application of mesenchymal stem cells derived from the umbilical cord or Wharton’s jelly and their extracellular vesicles in the treatment of various diseases. Tissue and Cell, 89, 102415. https://doi.org/10.1016/j.tice.2024.102415
Pittenger, M. F., Discher, D. E., Péault, B. M., Phinney, D. G., Hare, J. M., & Caplan, A. I. (2019). Mesenchymal stem cell perspective: Cell biology to clinical progress. npj Regenerative Medicine, 4(1), 22. https://doi.org/10.1038/s41536-019-0083-6
Shah, M., & Sarkar, D. (2024). HCC-related lncRNAs: Roles and mechanisms. International Journal of Molecular Sciences, 25(1), 597. https://doi.org/10.3390/ijms25010597
Siddiqui, N. N., ul Haq, A., Siddiqui, O. A., & Khan, R. (2016). DNA methyltransferase 1, 3a, and 3b expression in hepatitis C associated human hepatocellular carcinoma and their clinicopathological association. Tumour Biology, 37(8), 10487–10497. https://doi.org/10.1007/s13277-016-4941-1
Sun, Z., Xue, S., Zhang, M., Xu, H., Hu, X., Chen, S., Liu, Y., Guo, M., & Cui, H. (2020). Aberrant NSUN2-mediated m5C modification of H19 lncRNA is associated with poor differentiation of hepatocellular carcinoma. Oncogene, 39(45), 6906–6919. https://doi.org/10.1038/s41388-020-01475-w
Syyam, A., Akbar, H. R., Jilkova, Z. M., & Afzal, S. (2023). Role of genetic and epigenetic modifications in the progression of hepatocellular carcinoma in chronic HCV patients. Livers, 3(1), 82–92. https://doi.org/10.3390/livers3010008
Tang, W., Chen, Z., Zhang, W., Cheng, Y., Zhang, B., Wu, F., Wang, Q., Wang, S., Rong, D., Reiter, F. P., et al. (2020). The mechanisms of sorafenib resistance in hepatocellular carcinoma: Theoretical basis and therapeutic aspects. Signal Transduction and Targeted Therapy, 5, 87. https://doi.org/10.1038/s41392-020-0187-x
Wali, A. F., Ansari, A. R., Mir, P. A., El-Tanani, M., Babiker, R., Hussain, M. S., Uppal, J., Zargar, A. I., & Mir, R. H. (2025). Epigenetic alterations in hepatocellular carcinoma: Mechanisms, biomarkers, and therapeutic implications. Pharmaceuticals, 18(9), 1281. https://doi.org/10.3390/ph18091281
Wang, N., Shi, J.-X., Bartneck, M., Dahl, E., & Wang, J. (2025). Stratification of hepatocellular carcinoma using N6-methyladenosine. Cancers, 17(13), Article 2220. https://doi.org/10.3390/cancers17132220
Wolinska, E., & Skrzypczak, M. (2021). Epigenetic changes affecting the development of hepatocellular carcinoma. Cancers, 13(17), Article 4237. https://doi.org/10.3390/cancers13174237
Xu, R.-Y., Ding, Z., Zhao, Q., Ke, T.-Y., Chen, S., Wang, X.-Y., Wang, Y.-Y., Sheng, M.-F., Wang, W., Long, N., Xu, Y.-Z., & Shao, W. (2022). An alternatively spliced variant of METTL3 mediates tumor suppression in hepatocellular carcinoma. Genes, 13(4), 669. https://doi.org/10.3390/genes13040669
Yan, C., Yang, M., Li, Z., Li, S., Hu, X., Fan, D., Zhang, Y., Wang, J., & Xiong, D. (2014). Suppression of orthotopically implanted hepatocarcinoma in mice by umbilical cord-derived mesenchymal stem cells with sTRAIL gene expression driven by AFP promoter. Biomaterials, 35(9), 3035–3043. https://doi.org/10.1016/j.biomaterials.2013.12.037
Yang, C., Guan, Z., Pang, X., Tan, Z., Yang, X., Li, X., & Guan, F. (2022). Desialylated mesenchymal stem cells-derived extracellular vesicles loaded with doxorubicin for targeted inhibition of hepatocellular carcinoma. Cells, 11(16), Article 2642.
Yu, Z., Luo, J., An, W., Wei, H., Li, M., He, L., Xiao, F., & Wei, H. (2023). N7-methylguanosine-related lncRNA prognostic signature in hepatocellular carcinoma. Current Oncology, 30, 444–447. https://doi.org/10.3390/curroncol30010035
Yu, Z., Luo, J., An, W., Wei, H., Li, M., He, L., Xiao, F., & Wei, H. (2025). Migrasome marker epidermal growth factor domain-specific O-GlcNAc transferase: Pan-cancer angiogenesis biomarker and the potential role of circ_0058189/miR-130a-3p/EOGT axis in hepatocellular carcinoma progression and sorafenib resistance. Biomedicines, 13(4), 773.
Yuan, M., Yin, Z., Wang, Z., Xiong, Z., Chen, P., Yao, L., Liu, P., Sun, M., Shu, K., Li, L., et al. (2025). Modification of MSCs with aHSCs-targeting peptide pPB for enhanced therapeutic efficacy in liver fibrosis. Biomaterials, 321, 123295.
Yuan, X., Zhang, Q., Li, Z., Zhang, X., Bao, S., Fan, D., Ru, Y., Dong, S., Zhang, Y., Zhang, Y., et al. (2016). Mesenchymal stem cells deliver and release conditionally replicative adenovirus depending on hepatic differentiation to eliminate hepatocellular carcinoma cells specifically. Cancer Letters, 381(1), 85–95.
Zhang, B., Shan, H., Li, D., Li, Z.-R., Zhu, K.-S., & Jiang, Z.-B. (2012). The inhibitory effect of MSCs expressing TRAIL as a cellular delivery vehicle in combination with cisplatin on hepatocellular carcinoma. Cancer Biology & Therapy, 13(12), 1175–1184.
Zhang, Y., Liu, J., Lv, Y., Zhang, C., & Guo, S. (2019). LncRNA MEG3 suppresses hepatocellular carcinoma in vitro and vivo studies. American Journal of Translational Research, 11(7), 4089–4099.
Zhou, X., Huang, Y., Zhang, X., Guan, W., Zhang, F., & Hao, H. (2025). Epitranscriptomic regulation of Hepatitis B Virus by RNA 5-methylcytosine: Functions, mechanisms, and therapeutic potential. Viruses, 17(9), 1159. https://doi.org/10.3390/v17091159