Objective To investigate the effects of prostaglandin E1 ( PGE1) on liver function in rats with fulminant hepatic failure ( FHF), and to explore its regulatory effects on the eukaryotic translation-initiation factor 2α (eIF2α) / activating transcription factor 4 (ATF4) / C/ EBP homologous protein (CHOP) pathway. Methods Overall, 90 specific pathogen-free Sprague-Dawley rats were divided into control, model, positive control, low-, medium-, and high- dose PGE1 groups according to the random number table method . Except for the control group, all rats were intraperitoneally injected with D-galactosamine (D-GalN)-lipopolysaccharide (LPS) to establish the FHF rat model, and the control group received an intraperitoneal injection of the same volume of normal saline. At 6 hours after modeling, the positive control group and low-, medium-, and high-dose PGE1 groups were administered a tail vein injection of 1. 36 mg / kg hepatocyte growth promoting factor and 12. 5, 25, or 37. 5 μg / kg PGE1, respectively, once a day for 3 consecutive days. The control group and the model group were administered a tail vein injection of the same volume of normal saline. The rats were euthanized at 72 hours after modeling and abdominal aorta blood was collected. The serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) were measured. Liver tissues were dissected and stained with hematoxylin and eosin ( HE) to observe pathological changes. mRNA and protein levels of eIF2α/ ATF4 / CHOP / caspase-3 were detected by real-time fluorescence quantitative PCR (qRT-PCR) and Western blot was used to measure phosphorylated-eIF2α ( p-eIF2α) protein levels. Results Compared with the control group, hepatocytes in the model group showed extensive degeneration and focal necrosis, and the central venous was damaged. The levels of ALT, AST, and TBIL in serum, mRNA levels of eIF2α, ATF4, CHOP, and caspase-3, and protein levels of p-eIF2α/ eIF2α, ATF4, CHOP, and caspase-3 in liver tissues were higher (P< 0. 05). Compared with the model group, the damage to hepatocytes and the number of necrotic cells were decreased in the positive control, low-, medium-, and high-dose PGE1 groups. The levels of ALT, AST, and TBIL in serum, mRNA levels of eIF2α, ATF4, CHOP, and caspase-3 and protein levels of p-eIF2α/ eIF2α, ATF4, CHOP, and caspase-3 in liver tissues were lower (P< 0. 05). With an increase in PGE1 dosage, the levels of ALT, AST, and TBIL in serum, mRNA levels of eIF2α, ATF4, CHOP, and caspase-3 and protein levels of p-eIF2α/ eIF2α, ATF4, CHOP, and caspase-3 in the liver tissues of low-, medium-, and high-dose PGE1 groups were decreased (P< 0. 05) dose-dependently. Compared with the positive control group, the levels of ALT, AST, and TBIL in serum, mRNA levels of eIF2α, ATF4, CHOP, and caspase-3 and protein levels of p-eIF2α/ eIF2α, ATF4, CHOP, and caspase-3 in the liver tissues of the low- and medium-dose PGE1 groups were higher (P< 0. 05). However, there was no significant difference in the levels of ALT, AST, and TBIL in serum, mRNA levels of eIF2α, ATF4, CHOP, and caspase-3 and protein levels of p-eIF2α/ eIF2α, ATF4, CHOP, and caspase-3 in liver tissues between the positive control group and the high-dose PGE1 group ( P> 0. 05). Conclusions PGE1 may reduce the apoptosis of rat hepatocytes and protect the liver by inhibiting the expression of the eIF2α/ ATF4 / CHOP pathway, which may be a potential therapeutic target for FHF.