Objective:To explore the protective effect and its molecular mechanism of apoptosis signalregulating kinase 1(ASK1) inhibitor(GS-459679) on acetaminophen-induced liver injury in mice.Methods:The model of liver injury was established by administration of acetaminophen(APAP)(300 mg/kg,i.p.) on C57BL/6 mice.Forty-eight male C57BL/6 mice were randomly divided into four groups,consisting of control group,GS group(GS-459679,30 mg/kg,i.p.),APAPinduced group,and GS combined with APAP-induced group.For GS combined with APAPinduced group,mice were treated with GS 30 min prior to administration of APAP.After mice were euthanized at 6 h or 12 h.respectively,serum levels of alanine aminotransferase(ALT) and aspartate aminotransferase(AST) were analyzed,and mRNA levels of TNF- α,IL-6 and IL-1βwere tested.The activity of glutathione(GSH),oxidized GSH(GSSG) and malondialdehyde were quantified.In addition,ASK1,P-ASK1,JNK and P-JNK protein levels were tested in all groups.Results:The ASK1 and P-ASK1 levels were up-regulated in APAP-induced group.Compared to the control group,serum levels of ALT and AST.and mRNA levels of TNF- a,IL-6 and IL-1(3were increased in APAP-induced group.Meanwhile,the levels of MAD and GSSG.and the ratio of GSSG/GSH were higher and the JNK was activatedin APAP-induced group compared with that in control group.However,compared to APAP-induced group,GS combined with APAP-induced group displayed a decrease of protein expression levels of ASK 1,P-ASKI and P-JNK,a reduction of serum levels of ALT and AST,a decrease in TNF- a.IL-6 and IL-1(3 mRNA levels,and a low ration of GSSG/GSH.Conclusions:GS-459679 treatment effectively down-regulates ASK1 and P-ASK 1 expression.Addition of GS-459679 decreases the generation of liver metabolites and inflammatory factors,reduces oxidative stress reaction,inhibits JNK activation,and then protects the responsiveness to APAP-induced liver injury. Objective: To explore the protective effect and its molecular mechanism of apoptosis signalregulating kinase 1 (ASK1) inhibitor (GS-459679) on acetaminophen-induced liver injury in mice. Methods: The model of liver injury was established by administration of acetaminophen (APAP) (300 mg / kg, ip) on C57BL / 6 mice. Forty-eight male C57BL / 6 mice were randomly divided into four groups consisting of GS group (GS- 459679, 30 mg / kg, ip) group, and GS combined with APAP-induced group. For GS combined with APAP induced group, mice were treated with GS 30 min prior to administration of APAP. After mice were euthanized at 6 h or 12 h., serum levels of alanine aminotransferase ( ALT) and aspartate aminotransferase (AST) were analyzed, and mRNA levels of TNF- α, IL-6 and IL-1βwere tested.The activity of glutathione (GSH), oxidized GSH (GSSG) and malondialdehyde were quantified.In addition, ASK1 , P-ASK1, JNK and P-JNK protein levels were tested in all groups. Results: The ASK1 and P-ASK1 l evels were up-regulated in APAP-induced group. Compared to the control group, serum levels of ALT and AST. and mRNA levels of TNF-a, IL-6 and IL-1 (3were increased in APAP-induced group. the levels of MAD and GSSG. and the ratio of GSSG / GSH were higher and the JNK was activated in APAP-induced group compared with that in control group. However, compared to APAP-induced group, GS combined with APAP-induced group displayed a decrease of protein expression levels of ASK 1, P-ASKI and P-JNK, a reduction of serum levels of ALT and AST, a decrease in TNF-a.IL-6 and IL-1 (3 mRNA levels, and a low ration of GSSG / GSH.Conclusions: GS-459679 treatment effectively down-regulates ASK1 and P-ASK 1 expression. Condition of GS-459679 decreases the generation of liver metabolites and inflammatory factors, reduces oxidative stress reaction, inhibits JNK activation, and then protects the responsiveness to APAP-induced liver injury.