Targeting CASP8 and FADD-like apoptosis regulator ameliorates nonalcoholic steatohepatitis in mice and nonhuman primates

Nat Med. 2017 Apr;23(4):439-449. doi: 10.1038/nm.4290. Epub 2017 Feb 20.


Nonalcoholic steatohepatitis (NASH) is a progressive disease that is often accompanied by metabolic syndrome and poses a high risk of severe liver damage. However, no effective pharmacological treatment is currently available for NASH. Here we report that CASP8 and FADD-like apoptosis regulator (CFLAR) is a key suppressor of steatohepatitis and its metabolic disorders. We provide mechanistic evidence that CFLAR directly targets the kinase MAP3K5 (also known as ASK1) and interrupts its N-terminus-mediated dimerization, thereby blocking signaling involving ASK1 and the kinase MAPK8 (also known as JNK1). Furthermore, we identified a small peptide segment in CFLAR that effectively attenuates the progression of steatohepatitis and metabolic disorders in both mice and monkeys by disrupting the N-terminus-mediated dimerization of ASK1 when the peptide is expressed from an injected adenovirus-associated virus 8-based vector. Taken together, these findings establish CFLAR as a key suppressor of steatohepatitis and indicate that the development of CFLAR-peptide-mimicking drugs and the screening of small-molecular inhibitors that specifically block ASK1 dimerization are new and feasible approaches for NASH treatment.

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • Biopsy
  • Blood Glucose / metabolism
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics*
  • Dependovirus
  • Dimerization
  • Female
  • Gene Knock-In Techniques
  • Genetic Vectors
  • Hepatocytes / metabolism
  • Humans
  • Immunohistochemistry
  • Immunoprecipitation
  • Insulin Resistance / genetics
  • Interleukin-6 / metabolism
  • Liver / diagnostic imaging
  • Liver / metabolism*
  • Liver / pathology
  • MAP Kinase Kinase Kinase 5 / metabolism*
  • Macaca fascicularis
  • Male
  • Mice
  • Middle Aged
  • Mitogen-Activated Protein Kinase 8 / metabolism*
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Positron-Emission Tomography
  • Real-Time Polymerase Chain Reaction
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism
  • Ultrasonography
  • Young Adult


  • Blood Glucose
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • Mitogen-Activated Protein Kinase 8
  • MAP Kinase Kinase Kinase 5