Thymoquinone (TQ) is a main aromatic component of Nigella sativa L. seeds or Agastache rugosa (Fisch. & C.A.Mey.) Kuntze. The protective mechanism of TQ against acute liver injury induced by
acetaminophen (
APAP), however, remains unclear. We aimed to investigated the hepato-protective mechanism of TQ on the development of
APAP-induced acute liver injury. Male kunming mice were pretreated with TQ or
N-acetylcysteine (NAC) before a single
APAP injection. Human Chang liver cells were incubated with TQ,
SP600125 or
AICAR in presence of
APAP for 24 h. TQ pretreatment reduced levels of serum
aminotransferases and increased hepatic
glutathione and
glutathione peroxidase activities via inhibiting
CYP2E1 expression. TQ inhibited JNK, ERK and P38 phosphorylation induced by
APAP. Meanwhile, TQ inhibited PI3K/mTOR signaling activation and activated AMPK phosphorylation. Moreover, TQ prevented
APAP-induced hepatocytes apoptosis regulated by Bcl-2 and Bax. Furthermore, TQ inhibited STAT3 phosphorylation on
APAP-induced acute liver injury. In addition, TQ significantly inhibited P2X7R
protein expression and
IL-1 β release.
APAP-enhanced JNK phosphorylation and
APAP-suppressed AMPK phosphorylation were also observed in Chang liver cells, and these changes were recovered by pretreatment with TQ,
SP600125 and
AICAR. Our findings suggest that TQ may actively prevent
APAP-induced acute liver injury, and the effect may be mediated by JNK and AMPK signaling pathways.