<scp>RNA</scp> m ⁶ A methylation regulates sorafenib resistance in liver cancer through <scp>FOXO</scp> 3‐mediated autophagy

N6-methyladenosine (m⁶ A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary m⁶ A methyltransferase, is significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy-associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with m⁶ A modification of the FOXO3 mRNA 3'-untranslated region increasing its stability through a YTHDF1-dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3-mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m⁶ A-dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3-mediated m⁶ A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of m⁶ A modification in the resistance of HCC to sorafenib therapy.