In summary, our findings show that: (a) MAVS expression is increased in the liver of mouse models of MASLD and of people living with MASLD; (b) MAVS overexpression induced lipid accumulation; (c) inhibition of MAVS in the whole liver or specifically in hepatocytes of adult mice ameliorated TAp63α-induced and diet-induced liver steatosis; (d) the steatotic action of MAVS is mediated by ERK/TNFα/NFκβ; and (e) the posttranslational modification O-GlNAcylation is critical for MAVS-induced inflammation and lipid storage. This evidence concerns the gene MAVS and fatty liver disease.