Objective：To explore the protective effect of STF-08310，a specific inhibitor of inositol-requiring enzyme 1 endoribonuclease（IRE1）/spliced X-box binding protein 1（sXBP1）on liver ischemia-reperfusion（IR）injury and the possible mechanisms. Methods：Thirty C57BL/6 mice were randomly divided into 3 groups（10 in each group）：sham operation group（sham group），hepatic ischemia-reperfusion group（IR group），and STF-083010 pretreatment plus hepatic ischemia-reperfusion group（IR+STF-083010 group）. Levels of alanine aminotransferase（ALT） and aspartate aminotransferase（AST） in serum were detected by enzyme-linked immunosorbent assay（ELISA）. The histological damage of liver and the apoptosis of hepatocytes were evaluated by hematoxylin-eosin（HE） and TUNEL staining. The expression of interleukin（IL）-6，tumor necrosis factor（TNF）-α，and IL-1β mRNA were examined by RT-qPCR. sXBP1 and CHOP proteins in liver tissues were determined by immunohistochemistry and Western blot. Results：Compared to IR group，plasma ALT and AST levels in STF-083010+IR group were significantly lower（P < 0.01）. Liver tissues in STF-083010+IR group were more slightly damaged than those in IR group（P < 0.01）. The mRNA levels of IL-6，TNF-α and IL-1β in IR+STF-083010 group and the protein levels of sXBP1 and CHOP were significantly lower than those of IR group（P < 0.01）. Conclusion：Pretreatment of STF-083010 can alleviate liver IR injury by inhibiting sXBP1/CHOP signal pathway.