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Abstract Background Dietary fructose can rapidly cause fatty liver in animals through de novo lipogenesis (DNL) and contribute to the development and severity of nonalcoholic fatty liver disease (NAFLD). In response to diverse cellular insults including endoplasmic reticulum (ER) and oxidative stress, phosphorylation of the eukaryotic translation initiation factor 2 alpha subunit (eIF2α) attenuates general translation initiation, allowing cells to conserve resources and initiate adaptive gene expression to restore homeostasis. The present study aimed to investigate the role of eIF2α phosphorylation in protecting against NAFLD induced by high fructose ingestion in a hepatocyte-specific eIF2α-phosphorylation-deficient mouse model. Methods Hepatocyte-specific non-phosphorylatable (S51A) eIF2α knock-in (A/A;fTg/0;Cre Hep /0, A/A Hep ) mice were generated by crossing A/A;fTg/fTg mice with the floxed WT eIF2α transgene (fTg) with Alfp-Cre recombinase transgenic S/A;Cre Hep /0 (S/A-Cre Hep ) mice. Hepatocyte-specific eIF2α-phosphorylation-deficient 3-month-old mice or 12-month-old mice were fed a 60% high fructose diet (HFrD) for 16 or 5 wks, and the effects of eIF2α-phosphorylation deficiency on NADP/NADPH and GSSG/GSH levels, ROS-defense gene expression, oxidative damage, cell death, and fibrosis were observed. Results Prolonged fructose feeding to mice caused dysregulation of the unfolded protein response (UPR) sensor activation and UPR gene expression, and then led to decreased expression of several ROS defense genes including glutathione biogenesis genes. Nonetheless, these changes were not sufficient to induce the death of eIF2α phosphorylation-sufficient hepatocytes. However, there was a substantial increase in hepatocyte death and liver fibrosis in fructose-fed middle-aged mice deficient in hepatocyte-specific eIF2α phosphorylation because of diminished antioxidant capacity due to reduced expression of antioxidant enzymes (GPX1 and HO-1) and lower NADPH and glutathione levels, as well as a possible increase in ROS-induced damage from infiltrating NOX2-expressing leukocytes; all this led to a vicious cycle of hepatocyte death and leukocyte infiltration. Conclusion Our findings suggest that eIF2α phosphorylation maintains NADPH and GSH levels and controls the expression of ROS-defense genes, thereby protecting hepatocytes from oxidative stresses induced by fructose metabolism.