Objective:To investigate the hepatoprotective effect of Xijiao Dihuang Decoction(犀角地黄汤,XJDHD) on lipopolysaccharide (LPS)-and tumor necrosis factor alpha (TNF-α)-induced acute liver failure (ALF)as well as the underlying mechanism of action,and to clarify the key herbs and components of XJDHD.Methods:LPS/D-galactosamine (D-GaIN) or TNF-α/D-GaIN were intraperitoneally injected into C57BL/6J mice to induce ALF.Simultaneously,XJDHD or its individual herbs and components were orally administered.Survival rates,transaminase levels in serum,and hepatic histology were examined to evaluate the effects of XJDHD.The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay and real-time polymerase chain reaction were additionally performed to expound the mechanism underlying the anti-apoptotic activity of XJDHD.Results:Oral administration of XJDHD protected mice from lethal liver failure induced by LPS and TNF-α,with notable amelioration of liver injury in histology and a significant decrease in transaminase levels in serum.XJDHD significantly inhibited apoptosis of hepatocytes and enhanced expression of the antiapoptosis genes,c-Flip,lap1,Gadd45b and A20 (all P＜0.05).In addition,Rehmannia glutinosa Libosch.was identified as the key herb of XJDHD and galactose as the effective component of Rehmannia glutinosa Libosch.that protects against ALF.Conclusions:XJDHD inhibits TNF-α-induced apoptosis of hepatocytes by promoting the expression of nuclear factor κ B-regulated anti-apoptotic genes.Rehmannia glutinosa Libosch.may be the most effective herb of XJDHD and galactose is an active component in this protection.