m6A modification by METTL3 enhances BIRC6 translation to promote liver tumorigenesis

N6-methyladenosine (m6A) is the most prevalent internal modification of mRNA and is frequently dysregulated in cancer. However, the roles of m6A and its modifiers, such as the methyltransferase METTL3, remain controversial in primary tumors. We report that METTL3 is upregulated in the highly proliferative human S2 and mouse M2 subtypes of hepatocellular carcinoma (HCC). Integrated analyses of the RNA methylome, transcriptome and proteome identify Birc6 as a direct downstream target of Mettl3. Using CRISPR/dCas13b-mediated site-specific methylation, we demonstrate that m6A deposition at three conserved sites enhances Birc6 translation, thereby promoting degradation of caspase-7 and caspase-9 and suppressing apoptosis. Multiplexed in situ genome editing in mouse hepatocytes shows that Mettl3 promotes hepatocarcinogenesis in a cell-autonomous manner through Birc6. Together, our findings establish a functional link between METTL3-mediated m6A modification and BIRC6-mediated apoptosis inhibition in liver tumorigenesis, suggesting BIRC6 as a potential therapeutic target in HCC. Multi-omic profiling combined with multiplexed in situ genome editing in mouse hepatocytes demonstrates that METTL3 drives hepatocarcinogenesis via m⁶A modification of BIRC6 mRNA, identifying METTL3 and BIRC6 as promising therapeutic targets for hepatocellular carcinoma.