Fig. 1

Schematic overview of METTL14 deficiency-mediated mechanism of MASLD progression. Hepatocyte METTL14 plays a crucial role in the pathogenesis of the metabolic dysfunction-associated fatty liver disease (MAFLD). In MAFLD induced by a high-fat diet or hepatocyte-specific Mettl14 depletion, the METTL14-mediated m6A modification of Gls2 mRNA is reduced, leading to decreased translation dependent on YTHDF1. This reduction in GLS2 abundance diminishes the antioxidant capacity of hepatocytes, resulting in elevated levels of reactive oxygen species (ROS), lipid accumulation, and oxidative stress. Hepatocyte damage caused by these processes releases damage-associated molecular patterns (DAMPs), which in turn recruit and activate CX3CR1/MyD88/NF-κB signaling in Cx3cr1⁺Ccr2⁺ monocyte-derived macrophages. Consequently, the pro-inflammatory and pro-fibrotic factor S100A4 is produced and released, contributing to the activation of hepatic stellate cells and the induction of liver fibrosis. Taken together, loss of METTL14 in hepatocytes triggers hepatocyte damage, inflammation, and fibrosis, characteristic features of metabolic dysfunction-associated steatohepatitis (MASH), thereby suggesting it as a potential therapeutic target for the treatment of MAFLD. The figure is created with Biorender.com