Hepatic ischemia-reperfusion injury (HIRI) is a major complication of liver surgery, which causes a great threat to the life quality of the patients. Recent studies showed that HIRI is a dynamic process involving the hepatocyte injury and deterioration induced by ischemia/reperfusion (I/R) (Chen et al., 2021). In detail, the danger signal-associated molecular patterns (DAMPs) trigger an immune response and inflammatory reactions, which then leads to deterioration of tissue injury (Yazdani et al., 2017). On this basis, a positive feedback loop is formed between interleukin-22 (IL-22)-mediated inflammatory reaction and cellular death (Radaeva et al., 2004). However, the mechanism underlying inflammation regulation and tissue repairing during HIRI is still not well defined. Many lines of evidence indicated that IL-22/IL-22 receptor 1 (IL-22R1) pathway attenuates cardiac, hepatic and renal I/R injury by regulating inflammatory responses (Chestovich et al., 2012, Wu et al., 2020). IL-22 is the only known cytokine produced by immune cells that does not serve as a communicator between immune cells, but instead signals between immunocytes and epithelial cells, or directly to tissues (Wolk et al., 2004, Zenewicz, 2021). Hence, IL-22-medicated cellular communication is essential for the regulation of inflammation and tissue repairing (Wolk et al., 2004, Zenewicz, 2021).

As one of the most critical sites of energy metabolism, mitochondria are most sensitive to ischemia and hypoxia (Dambrova et al., 2021, Greco et al., 2020, Zhang et al., 2021). External stimuli such as hypoxia induce mitochondrial electron transport chain breakage, reactive oxygen species (ROS) generation, adenosine triphosphate (ATP) consumption, mitochondrial permeability transition pore opening, and mitochondrial membrane potential reduction (Dela Cruz and Kang, 2018). The damage of mitochondrial structure is responsible for the release of pro-apoptotic factors into the cytosol, induces the activation of Bcl-2, Bax and caspases, and eventually leads to the formation of apoptotic bodies (Abate et al., 2020). It has been confirmed that IL-22 inhibits mitochondrial apoptosis through increasing the activity of superoxide dismutase (SOD), maintaining mitochondrial membrane potential, decreasing the production of ROS and inhibiting the release of cytochrome C in cardiac I/R injuries (Che et al., 2021) and biliary I/R injuries (Bai et al., 2022). However, little information on the roles of IL-22 in mitochondrial apoptosis was available in HIRI.

IL-22 binds to its specific receptors to form IL-22/IL-22R1/IL-22R2 complex, which activates STAT3 dimers, induces the translocation into the nucleus, binds to the target genes and initiates gene transcription (de Oliveira Neto et al., 2008, Murano et al., 2014). Current studies have shown that the JAK2-STAT3 signaling pathway is involved in hepatic, cardiac, renal and cerebral I/R injuries (Liao et al., 2017, Zhang et al., 2019, Zhong et al., 2021). IL-22 acts by activating JAK2/STAT3 signaling, and the Bcl-2 promoter possesses several putative STAT3 DNA binding sites (Alas and Bonavida, 2001). Therefore, we hypothesized that IL-22 may attenuate HIRI by activating STAT3 and inhibiting apoptosis via mitochondrial pathways. To verify the above conjecture, this study constructed in vitro and in vivo models of HIRI models to analyze the changes of IL-22/IL-22R1/STAT3 pathway molecules. We also analyze the effects of exogenous IL-22 on mitochondrial functions, calcium overloading and mitochondrial apoptosis. This study expects to explore novel targets of HIRI to improve the efficacy of liver surgery and the survival rates of liver transplantation.