Hepatocytes are responsible for diverse metabolic activities in a liver.Proper ribosome biogenesis is essential to sustain the function of hepatocytes.There are approximately 200 factors involved in ribosome biogenesis;however,few studies have focused on the role of these factors in maintaining liver homeostasis.The digestive organ expansion factor (dejf) gene encodes a nucleolar protein Def that participates in ribosome biogenesis.In addition,Def forms a complex with cysteine protease Calpain3 (Capn3) and recruits Capn3 to the nucleolus to cleave protein targets.However,the function of Def has not been characterized in the mammalian digestive organs.In this report,we show that conditional knockout of the mouse defgene in hepatocytes causes cell morphology abnormality and constant infiltration of inflammatory cells in the liver.As age increases,the defconditional knockout liver displays multiple tissue damage foci and biliary hyperplasia.Moreover,partial hepatectomy leads to sudden acute death to the defconditional knockout mice and this phenotype is rescued by intragastric injection of the anti-inflammation drug dexamethasone one day before hepatectomy.Our results demonstrate that Def is essential for maintaining the liver homeostasis and liver regeneration capacity in mammals.