Hepatic ischemia-reperfusion (I/R) injury is a complex pathophysiological process that often times occurs in liver transplantation, hepatectomy, and ischemic shock. Aberrant activation of inflammatory responses has been implicated in hepatic I/R injury. In this study, we aimed to investigate the role of circadian clock gene Rev-erb alpha (a well-known regulator of inflammation) in hepatic I/R injury. We first showed that Rev-erb alpha ablation sensitized mice to hepatic I/R injury as evidenced by higher levels of plasma alanine aminotransferase and aspartate aminotransferase, an increased histological score, as well as enhanced hepatic myeloperoxidase activity in Rev-erb alpha(-/-) mice. More severe hepatic I/R injury in Rev-erb alpha(-/-) mice was accompanied by higher expression of pro-inflammatory cytokines, exacerbated activation of Nlrp3 inflammasome, and more extensive infiltration of inflammatory cells. Moreover, pharmacological activation of Rev-erb alpha by SR9009 significantly alleviated the hepatic damage and inflammatory responses. In addition, I/R operation started at ZT18 (corresponding to low Rev-erb alpha expression) caused more severe liver damage and inflammatory responses in wild-type mice as compared to operation started at ZT6 (corresponding to high Rev-erb alpha expression), supporting a protective effect of Rev-erb alpha on hepatic I/R injury. Collectively, Rev-erb alpha protects hepatic I/R injury probably via repression of inflammatory re-sponses, and targeting Rev-erb alpha may be a promising approach for management of hepatic I/R injury. (C) 2020 Elsevier Inc. All rights reserved.