Protective Effects of Fisetin on Hepatic Ischemia-reperfusion Injury Through Alleviation of Apoptosis and Oxidative Stress

Background and aims: Hepatic ischemia-reperfusion injury (IRI) is the main leading cause of morbidity and mortality of patients after liver surgery and transplantation. Fisetin, a kind of flavonoid, has been reported to protect against myocardial and cerebral IRI. However, the effects of fisetin on liver IRI were poorly investigated.

Methods: C57BL/6 mice were used to establish the liver IRI model in vivo. Intraperitoneal injection of fisetin was performed one hour before IR treatment (1 h ischemia and 6h reperfusion). In vitro experimental study was conducted using AML-12 hepatocytes with 1 h hypoxia and 12 h reoxygenation (HR) treatment. Tissue damage was evaluated through serum AST and ALT levels and hematoxylin-eosin (HE) staining. Cell Apoptosis was assessed by TUNEL staining and protein levels of Bax, Bcl-2, cleaved-caspase-3, and cleaved-PARP. Oxidative stress was evaluated by ROS and MDA levels and the activity of SOD and GSH-Px. Immunohistochemistry and immunofluorescence assay were performed to observe the translocation of Nrf2 from the cytoplasm into the nucleus.

Results: The histopathological assessment showed that fisetin attenuated IR-induced liver damage obviously. Besides, fisetin served a protective role in IR liver to alleviate cell Apoptosis and oxidative stress in vivo and in vitro. Introduction of high concentration of fisetin promoted the translocation of Nrf2 from the cytoplasm into the nucleus, increasing protein expression of its downstream elements, at least HO-1 in IR liver tissues and hepatocytes after HR. Inhibition of Nrf2 could reverse the effects of fisetin on cell viability, cell Apoptosis, and also oxidative stress of HR hepatocytes, suggesting that Nrf2 signaling was necessary in fisetin-mediated regulations of liver IRI.

Conclusion: Fisetin alleviates liver damage, cell Apoptosis, and oxidative stress induced by liver IRI, at least through Nrf2/HO-1 signaling pathway, suggesting that fisetin could be considered as a targeted drug for liver IRI treatment.