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BACKGROUND:?Increasing evidence suggests that the inactiva-tion of cathepsin B attenuates hepatocyte apoptosis and liver damage. This study aimed to investigate the protective effects of a cathepsin B inhibitor (CA-074me) on lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced acute hepatic failure (AHF) in mice. METHODS:?Mice were intraperitoneally injected with a combination of LPS/D-GalN to induce AHF with or without CA-074me pretreatment. The cumulative survival rates were calculated 48 hours after the induction of AHF. As well as changes in biochemical indicators and liver histology, hepatocyte apoptosis was assessed using a TUNEL method. Serum tumor necrosis factor-α(TNF-α) production, caspase-3, caspase-8, and caspase-9 activity was evaluated. Cytosolic cytochrome c and Bcl-2 expression were measured by Western blotting. RESULTS:?The marked elevation in serum aminotransferase activity and prothrombin time found in LPS/D-GalN-treated mice was signiifcantly improved by pretreatment with CA-074me. The efifcacy of CA-074me was also conifrmed by histological analysis and TUNEL assay. The survival rate signiifcantly improved in LPS/D-GalN-induced mice given CA-074me compared with untreated mice. LPS/D-GalN-induced caspase-3 and caspase-9 activation was remarkably suppressed by CA-074me. However, the increased levels of serum TNF-α and elevated caspase-8 activity in AHF mice were not signiifcantly reduced by CA-074me. Moreover, CA-074me sharply reduced the increased expression of cytosolic cytochrome c and markedly augmented Bcl-2 expression. CONCLUSION:?These results suggest that CA-074me has a protective effect in acute hepatic failure induced by LPS/D-GalN.