The GSK3β inhibitor attenuate APAP-induced liver injury by regulating PGC1α-mediated oxidative stress

Acetaminophen (N-acetyl-p-aminophenol, APAP), is the most frequent cause of drug-induced liver injury. Reducing APAP-induced oxidative stress is an effective strategy to improve acute liver injury. Glycogen synthase kinase-3β (GSK3β), is sensitive to redox homeostasis and is involved in oxidative stress-related injuries. However, whether GSK3β influences APAP-induced acute liver injury by modulating oxidative stress remains incompletely elucidated. To address this issue, we developed a novel GSK3β inhibitor 10b and conducted a series of studies to elucidate the role and specific mechanism of GSK3β in APAP-induced liver injury. The GSK3β inhibitor 10b suppressed the reduction of inhibitory phosphorylation levels of GSK3β, stabilized the protein level of PGC1α, protected mitochondrial function in hepatocytes, alleviated oxidative stress, and improved acute liver injury induced by APAP. Importantly, GSK3β siRNA clearly reversed the protection of 10b on APAP-stimulated AML12 cells. In conclusion, the GSK3β inhibitor 10b attenuate APAP-induced liver injury by regulating PGC1α-mediated oxidative stress.