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Interleukin-22 (IL-22) has been proven to exhibit a protective role in hepatic ischemia-reperfusion injury (HIRI). This study aimed to explore the change of IL-22 and IL-22 receptor 1 (IL-22R1) axis in HIRI and its role in mitochondrial apoptosis associated with STAT3 activation. I/R mice were examined for the expression of IL-22, IL-22R1 and IL-22BP. The roles of IL-22 in hepatic histopathology and oxidative stress injuries (ALT, MDA and SOD) were determined. Oxidative stress damages of AML-12 cells were induced by H 2 O 2 , and were indicated by apoptosis, Ca2+ concentration, and mitochondrial function. The effects of IL-22 on p-STAT3Try705 were analyzed. We found that the expression of IL-22, IL-22R1, and IL-22BP was elevated 24 h after I/R induction, while decreased 48 h after I/R induction. Furthermore, we also discovered that IL-22 rescued the morphological damages and dysfunction of hepatocytes induced by H 2 O 2 , which were antagonized by IL-22BP, an endogenous antagonist of IL-22. Additionally, increased levels of Ca2+ concentration, MDA, ROS, apoptosis and mitochondrial dysfunction were noticed in H 2 O 2 -treated hepatocytes. However, IL-22 ameliorated the effects of I/R or H 2 O 2. The protective effects of IL-22 were reversed by AG490, a specific antagonist of STAT3. In conclusion, our results indicated that IL-22 inhibited I/R-induced oxidative stress injury, Ca2+ overload, and mitochondrial apoptosis via STAT3 activation. • Exogenous IL-22 improves the morphology and function of hepatocytes. • IL-22BP, an antagonist of IL-22, antagonizes the hepatoprotective effects of IL-22. • IL-22 attenuates mitochondrial dysfunction and DNA damage in hepatocytes. • The effects of IL-22 are linked to the activation of JAK2/STAT3 signaling pathway. [ABSTRACT FROM AUTHOR]