These findings indicate that protein farnesylation plays an important role in the development of inflammatory liver failure. == Acknowledgments == Financial SupportThis work was supported by grants from Shriners Hospitals for Children to M. (ALT) and aspartic aminotransferase (AST) levels leading to significant mortality in mice. Tipifarnib inhibited GalN/LPS-induced caspase 3 activation, inflammatory cytokine production, and c-Jun N-terminal Kinase (JNK) phosphorylation in the liver. On the other hand, Tipifarnib upregulated anti-apoptotic protein, Bcl-xL, in the liver after GalN/LPS challenge. Tipifarnib also protected primary hepatocytes from GalN/tumor necrosis factor- (TNF-)-induced cell death by inhibiting caspase 3 activation and upregulating anti-apoptotic proteins. GalN/LPS-induced liver injury was associated with increased protein farnesylation in the liver. Tipifarnib prevented protein farnesylation in the liver and markedly attenuated liver injury and mortality in GalN/LPS-challenged mice. These results suggest that protein farnesylation is a novel potential molecular target to prevent hepatocyte death and acute inflammatory liver failure in fulminant hepatitis. == Introduction == Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Although a variety of insults including viral infection and NG52 drugs can cause ALF, the resulting clinical picture is remarkably similar across the different etiologies, reflecting common patterns NG52 of response of the innate immune system and the resulting inflammation in the liver. Management of severe ALF continues to be one of the most challenging problems in clinical medicine. Liver transplantation has been shown to be the most effective therapy, but the F3 procedure is limited by shortage of donor organs combined with the disadvantage of required immunosuppressant treatment (1,2). New preventive and/or therapeutic strategies need to be developed to improve the clinical outcome of patients with ALF. Statins inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. However, statins have been shown to exert pleiotropic beneficial effects independent of their cholesterol-lowering effects. For example, statins have been shown to prevent septic shock in animal models (3). Statins reduce the biosynthesis of not only cholesterol but also farnesyl pyrophosphate, which is the precursor NG52 of cholesterol as well as the substrate of protein farnesylation. Protein farnesylation is a lipid modification of cysteine residues in the CAAX motif located in the carboxyl terminus of proteins (where C is cysteine, A is aliphatic amino acid, and X is any amino acid, but usually serine, methionine, glutamine, or alanine). Farnesyltransferase (FTase) is an enzyme that catalyzes the covalent attachment of a farnesyl group, from farnesyl pyrophosphate to the cysteine thiols in the C-terminal CAXX consensus sequences. In many proteins, farnesylation serves as a critical regulatory mechanism of protein function, such as maturation, activation, protein-protein interaction, and membrane localization. Proteins that are known to be affected by farnesylation include the Ras family small G-proteins, lamin A, the nuclear protein, and the CENP, the centrometric protein (4). We have previously demonstrated that FTase inhibitors reduced mortality after endotoxin shock or polymicrobial sepsis induced by cecum ligation and puncture in mice (4,5). Of notice, NG52 FTase inhibitors prevented LPS-induced caspase 3 cleavage and activation of JNK in the mouse liver (5). These observations show that protein farnesylation plays a role in LPS-induced liver damage. Nonetheless, a role of protein farnesylation in ALF has not yet been analyzed. The security and tolerability of the FTase inhibitors, including tipifarnib, have been confirmed in the medical studies (6), while the combined results were reported about the effectiveness of the FTase inhibitors in malignancy and hematologic malignancies (7). To elucidate the part of protein farnesylation in ALF, we examined the effects of tipifarnib, a FTase inhibitor, inside a mouse model of ALF induced by GalN/lipopolysaccharide (LPS). GalN sensitizes the liver towards additional stimuli in part reflecting the part of uridine comprising compounds in hepatic biotransformation. Co-administration of LPS and GalN causes hepatocyte apoptosis, leading to ALF (8,9). Here, we display that tipifarnib, a FTase inhibitor, prevented apoptotic hepatocyte death and reduced mortality in mice subjected to GalN/LPS-induced ALF. == Materials and Methods == == Animals and acute liver failure model == After authorization from the Massachusetts general Hospital Subcommittee on Study Animal Care, all animal experiments were performed in accordance with the guidelines of.