In this study, we identified the functions of GRHL2 in NAFLD and further found that SIRT1 down‐regulation induced by GRHL2‐dependent miR‐200 or MAPK signalling pathway activated by GRHL2 exacerbated liver fibrosis and intestinal mucosal barrier dysfunction in NAFLD. This evidence concerns the gene SIRT1 and metabolic dysfunction-associated steatotic liver disease.