METTL3 drives NAFLD-related hepatocellular carcinoma and is a therapeutic target for boosting immunotherapy.

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor of hepatocellular carcinoma (HCC). However, the mechanism and target therapy of NAFLD-HCC are still unclear. Here, we identify that the N⁶-methyladenosine (m⁶A) methyltransferase METTL3 promotes NAFLD-HCC. Hepatocyte-specific Mettl3 knockin exacerbated NAFLD-HCC formation, while Mettl3 knockout exerted the opposite effect in mice. Single-cell RNA sequencing revealed that METTL3 suppressed antitumor immune response by reducing granzyme B (GZMB⁺) and interferon gamma-positive (IFN-γ⁺) CD8⁺ T cell infiltration, thereby facilitating immune escape. Mechanistically, METTL3 mediates sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) mRNA m

SUBMITTER: Pan Y 

PROVIDER: S-EPMC10439254 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature