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Peroxisome proliferator-activated receptors (PPARs) α and γ have been shown to be protective in hepatic ischemia/reperfusion (I/R) injury. However, the precise role of PPAR γ coactivator-1 α (PGC-1 α ), which can coactivate both of these receptors, in hepatic I/R injury, remains largely unknown. This study was designed to test our hypothesis that PGC-1 α is protective during hepatic I/R injury in vitro and in vivo. Our results show that endogenous PGC-1 α is basally expressed in normal livers and is moderately increased by I/R. Ectopic PGC-1 α protects against hepatic I/R and hepatocyte anoxia/reoxygenation (A/R) injuries, whereas knockdown of endogenous PGC-1 α aggravates such injuries, as evidenced by assessment of the levels of serum aminotransferases and inflammatory cytokines, necrosis, apoptosis, cell viability, and histological examination. The EMSA assay shows that the activation of PPAR α and PPAR γ is increased or decreased by the overexpression or knockdown of PGC-1 α , respectively, during hepatic I/R and hepatocyte A/R injuries. In addition, the administration of specific antagonists of either PPAR α (MK886) or PPAR γ (GW9662) can effectively decrease the protective effect of PGC-1 α against hepatic I/R and hepatocyte A/R injuries. We also demonstrate an important regulatory role of PGC-1 α in reactive oxygen species (ROS) metabolism during hepatic I/R, which is correlated with the induction of ROS-detoxifying enzymes and is also dependent on the activations of PPAR α and PPAR γ . These data demonstrate that PGC-1 α protects against hepatic I/R injury, mainly by regulating the activation of PPAR α and PPAR γ . Thus, PGC-1 α may be a promising therapeutic target for the protection of the liver against I/R injury., Competing Interests: The authors declare no competing financial interests., (Copyright © 2021 Chaoqun Wang et al.)