LAUSR

BACKGROUND & AIMS p21 activated kinase 4 (PAK4), an oncogenic protein, has emerged as a promising target for anti-cancer drug development. Its role in oxidative stress conditions, however, remains elusive. We investigated the effects of PAK4 signaling on hepatic ischemia/reperfusion (I/R) injury. APPROACH & RESULTS Hepatocyte- and myeloid-specific Pak4 knockout (KO) mice and their littermate controls were subjected to a partial hepatic I/R injury. We manipulated the catalytic activity of PAK4, either through genetic engineering (gene knockout, overexpression of wild-type or dominant-negative kinase) or pharmacological inhibitor, coupled with a readout of nuclear factor erythroid 2-related factor 2 (Nrf2) activity to test the potential function of PAK4 on hepatic I/R injury. PAK4 expression was markedly upregulated in liver during hepatic I/R injury in mice and humans. Deletion of PAK4 in hepatocytes, but not in myeloid cells, ameliorated liver damages, as demonstrated in the decrease in hepatocellular necrosis and inflammatory responses. Conversely, the forced expression of wild-type PAK4 aggravated the pathological changes. PAK4 directly phosphorylated Nrf2 at T369, and it led to its nuclear export and proteasomal degradation, and all of which impaired the antioxidant responses in hepatocytes. Nrf2 silencing in liver abolished the protective effects of PAK4 deficiency. A newly developed PAK4 inhibitor protected the mice from hepatic I/R injury. CONCLUSIONS PAK4 phosphorylates Nrf2 and suppresses its transcriptional activity. Genetic or pharmacological suppression of PAK4 alleviates hepatic I/R injury. Thus, PAK4 inhibition may represent a promising intervention against I/R induced liver injury.