25-Hydroxycholesterol mitigates hepatic ischemia reperfusion injury via mediating mitophagy

Hepatic ischemia reperfusion (I/R) injury remains a major obstacle in liver transplantation, however an effective treatment to mitigate this injury is lacking. 25-Hydroxycholesterol (25HC) is a kind of oxysterol involved in inflammatory and immune responses. However, its function and the underlying mechanism on rat hepatic I/R injury has not been explored. A well-established rat model of partial warm ischemia reperfusion injury was performed. 25HC was intraperitoneally administrated 4 h before ischemia. The results verified that 25HC pretreatment effectively mitigated liver I/R injury, which was demonstrated by lower serum levels of transaminases, histology injury score and less apoptosis. Mechanistically, 25HC pretreatment activated PINK1/Parkin dependent mitophagy and inhibited the NLRP3 inflammasome. Via using mitophagy inhibitor 3-methyladenine (3-MA), we further found that 3-MA counteracted the protective effect of 25HC on hepatic I/R injury and the NLRP3 inflammasome. In conclusion, 25HC pretreatment ameliorates rat hepatic I/R injury, and this protective effect may be dependent on activating mitophagy and inhibiting NLRP3 inflammasome activation.