METTL3 Knockout Accelerates Hepatocarcinogenesis via Inhibiting Endoplasmic Reticulum Stress Response

Hepatocellular carcinoma (HCC) is among the most common cause of cancer-related death worldwide. Previous studies showed that N6-methyladenosine (m⁶A), the most abundant chemical modification in eukaryotic RNAs, is implicated in HCC progression. Using liver-specific conditional knockout mice, here we found that loss of METTL3, the core catalytic subunit of m⁶A methyltransferase, significantly promoted hepatic tumor initiation under various oncogenic challenges, contrary to the previously reported oncogenic role of METTL3 in liver cancer cell lines or xenograft models. Mechanistically, METTL3 deficiency accelerates HCC initiation by inhibiting m6A/Manf/endoplasmic reticulum (ER) stress response. Our findings suggest a tumor-suppressive role for METTL3 in the early stages of HCC, emphasizing the importance of understanding the dynamic role of epigenetic regulation in tumorigenesis and targeted therapy. RNA-sequencing were conducted on liver tissues from Control and liver-specific METTL3 inducible knockout (Mettl3 cKO) mice 3 weeks post-hydrodynamic tail vein injection of c-MYC/sgP53 plasmids (4 individuals per group)