The Role of METTL3-Mediated m⁶A Methylation in Hepatocellular Carcinoma Progression and Treatment.
4 affiliations
- 1Department of Marine Bioscience and Environment, College of Ocean Science and Technology, Korea Maritime & Ocean University, Busan 49112, Republic of Korea.
- 2Section of Hematology, Department of Internal Medicine and Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520, USA.
- 3Department of Biochemistry, Kosin University College of Medicine, Seo-Gu, Busan 49267, Republic of Korea.
- 4Department of Gastroenterology, Ajou University School of Medicine, 164 Worldcup-Ro, Yeongtong-Gu, Suwon 16499, Republic of Korea.
Abstract
Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Emerging evidence has established N⁶-methyladenosine (m⁶A) RNA methylation as a key epitranscriptomic mechanism underlying hepatocarcinogenesis. Methyltransferase-like 3 (METTL3), the catalytic core of the m⁶A methyltransferase complex (MTC), forms a heterodimer with METTL14 and cooperates with auxiliary components of the MTC to deposit m⁶A modifications that modulate mRNA stability, splicing, nuclear export, and translation. In this review, we comprehensively summarize the current understanding of METTL3 biology in HCC, focusing on its structure, assembly within the MTC, regulation of coding and non-coding RNAs, and its roles in driving key oncogenic signaling cascades, such as JAK/STAT3, PI3K/AKT/mTOR, Wnt/β-catenin, Hippo/YAP, Notch, Hedgehog, and epithelial-mesenchymal transition. In addition, we discussed how METTL3 remodels the tumor immune microenvironment (TIME) by regulating immune responses and metabolic pathways promoting immune evasion and therapy resistance. Therapeutic strategies targeting METTL3-including small-molecule inhibitors, CRISPR-Cas9 approaches, combination immunotherapy, and tumor-selective delivery systems-are discussed together with the challenges that continue to limit clinical translation. Collectively, these findings position METTL3 as a central epitranscriptomic regulator of HCC progression; however, further mechanistic and clinical validation remains necessary to establish its utility as a therapeutic target and prognostic biomarker.
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BibTeX
@article{maduranga2026role,
title = {{The Role of METTL3-Mediated m⁶A Methylation in Hepatocellular Carcinoma Progression and Treatment.}},
author = {Bala Gamage Nalaka Hasith Maduranga and Hee Doo Yang and Su In Lee and Jung Woo Eun and Sun-Young Lim and Hyung Seok Kim and Jee-Yeong Jeong},
journal = {Epigenomes},
year = {2026},
month = oct,
doi = {10.3390/epigenomes10040063},
url = {https://europepmc.org/article/MED/42924722},
note = {CC BY},
}
RIS
TY - JOUR
TI - The Role of METTL3-Mediated m⁶A Methylation in Hepatocellular Carcinoma Progression and Treatment.
AU - Bala Gamage Nalaka Hasith Maduranga
AU - Hee Doo Yang
AU - Su In Lee
AU - Jung Woo Eun
AU - Sun-Young Lim
AU - Hyung Seok Kim
AU - Jee-Yeong Jeong
PY - 2026
DA - 2026/10/04
JO - Epigenomes
DO - 10.3390/epigenomes10040063
UR - https://europepmc.org/article/MED/42924722
AB - Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Emerging evidence has established N⁶-methyladenosine (m⁶A) RNA methylation as a key epitranscriptomic mechanism underlying hepatocarcinogenesis. Methyltransferase-like 3 (METTL3), the catalytic core of the m⁶A methyltransferase complex (MTC), forms a heterodimer with METTL14 and cooperates with auxiliary components of the MTC to deposit m⁶A modifications that modulate mRNA stability, splicing, nuclear export, and translation. In this review, we comprehensively summarize the current understanding of METTL3 biology in HCC, focusing on its structure, assembly within the MTC, regulation of coding and non-coding RNAs, and its roles in driving key oncogenic signaling cascades, such as JAK/STAT3, PI3K/AKT/mTOR, Wnt/β-catenin, Hippo/YAP, Notch, Hedgehog, and epithelial-mesenchymal transition. In addition, we discussed how METTL3 remodels the tumor immune microenvironment (TIME) by regulating immune responses and metabolic pathways promoting immune evasion and therapy resistance. Therapeutic strategies targeting METTL3-including small-molecule inhibitors, CRISPR-Cas9 approaches, combination immunotherapy, and tumor-selective delivery systems-are discussed together with the challenges that continue to limit clinical translation. Collectively, these findings position METTL3 as a central epitranscriptomic regulator of HCC progression; however, further mechanistic and clinical validation remains necessary to establish its utility as a therapeutic target and prognostic biomarker.
SN - 2075-4655
ER -