Notably, nutritional stress-induced deSUMOylation of FoxA1 facilitated Mdm2-mediated ubiquitylation and degradation of FoxA1, and consequently restrained transcription and expression of Sirt6, providing insights into the upstream modulatory mechanism of Sirt6 in NAFLD. This evidence concerns the gene SIRT6 and metabolic dysfunction-associated steatotic liver disease.