Rabbit hemorrhagic disease virus (RHDV) causes lethal fulminant hepatitis closely resembling acute liver failure (ALF) in humans. In this study, we investigated whether cardiotrophin-1 (CT-1), a cytokine with hepatoprotective properties, could attenuate liver damage and prolong survival in virus-induced ALF. Twentyfour rabbits were infected with 2 ؋ 10 4 hemagglutination units of RHDV. Twelve received five doses of CT-1 (100 g/kg) starting at 12 h postinfection (hpi) (the first three doses every 6 h and then two additional doses at 48 and 72 hpi), while the rest received saline. The animals were analyzed for survival, serum biochemistry, and viral load. Another cohort (n ؍ 22) was infected and treated similarly, but animals were sacrificed at 30 and 36 hpi to analyze liver histology, viral load, and the expression of factors implicated in liver damage and repair. All infected rabbits that received saline died by 60 hpi, while 67% of the CT-1-treated animals survived until the end of the study. Treated animals showed improved liver function and histology, while the viral loads were similar. In the livers of CT-1-treated rabbits we observed reduction of oxidative stress, diminished PARP1/2 and JNK activation, and decreased inflammatory reaction, as reflected by reduced expression of tumor necrosis factor alpha, interleukin-1, Toll-like receptor 4, VCAM-1, and MMP-9. In addition, CT-1-treated rabbits exhibited marked upregulation of TIMP-1 and increased expression of cytoprotective and proregenerative growth factors, including platelet-derived growth factor B, epidermal growth factor, plateletderived growth factor receptor , and c-Met. In conclusion, in a lethal form of acute viral hepatitis, CT-1 increases animal survival by attenuating inflammation and activating cytoprotective mechanisms, thus representing a promising therapy for ALF of viral origin.Acute liver failure (ALF) arises as a result of extensive hepatocellular damage that exceeds the liver's capacity to regenerate. Depending on the interval between the onset of jaundice and that of encephalopathy, ALF can be categorized into hyperacute (less than 1 week), acute (between 1 and 4 weeks) and subacute (more than 4 weeks). Etiologic factors include viral infections, drugs, biological toxins, metabolic disorders, and ischemia, but it is not unusual for this syndrome to arise without any known causative agent (22).ALF is one of the most challenging human conditions requiring critical care. Therapy is merely supportive and oriented to the correction of complications. Survival is poor and liver transplantation is the only definitive treatment for patients with severe ALF. However, the indication for liver transplantation relies on prognostic assessment, and this lacks accuracy. In transplanted patients mortality is about 10%, but ca. 30% of patients with ALF die without having access to transplantation (24). Thus, novel medical treatments for this condition are urgently needed. With the exception of N-acetylcysteine, which can prevent glutathione depletion...