It has been reported that the transcription of FGF21 is controlled by nutritional status, such as fasting and refeeding regimens.[45] Our previous studies revealed that SIRT1‐mediated activation of FGF21 prevents liver steatosis caused by fasting.[26] Here, the inhibition of SIRT1 by EX527 prominently abolishes the expression and production of hepatic FGF21, leading to a more severe ALD phenotypes. Here, FGF21 is linked to fatty liver disease.