The Role of METTL3-Mediated m6A Methylation in Hepatocellular Carcinoma Progression and Treatment

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.