Shc inhibitor idebenone ameliorates liver injury and fibrosis in dietary NASH in mice

J Biochem Mol Toxicol. 2021 Oct;35(10):e22876. doi: 10.1002/jbt.22876. Epub 2021 Aug 8.


Shc expression rises in human nonalcoholic steatohepatitis (NASH) livers, and Shc-deficient mice are protected from NASH-thus Shc inhibition could be a novel therapeutic strategy for NASH. Idebenone was recently identified as the first small-molecule Shc inhibitor drug. We tested idebenone in the fibrotic methionine-choline deficient (MCD) diet and the metabolic fast food diet (FFD) mouse models of NASH. In the fibrotic MCD NASH model, idebenone reduced Shc expression and phosphorylation in peripheral blood mononuclear cells and Shc expression in the liver; decreased serum alanine aminotransferase and aspartate aminotransferase; and attenuated liver fibrosis as observed by quantitative polymerase chain reaction (qPCR) and hydroxyproline quantification. In the metabolic FFD model, idebenone administration improved insulin resistance, and reduced inflammation and fibrosis shown with qPCR, hydroxyproline measurement, and histology. Thus, idebenone ameliorates NASH in two mouse models. As an approved drug with a benign safety profile, Idebenone could be a reasonable human NASH therapy.

Keywords: NASH; Shc; fibrosis; idebenone; inflammation.

MeSH terms

  • Alanine Transaminase / blood
  • Animals
  • Aspartate Aminotransferases / blood
  • Choline Deficiency / complications
  • Diet / adverse effects*
  • Disease Models, Animal
  • Fast Foods / adverse effects
  • Leukocytes, Mononuclear / metabolism
  • Liver / injuries
  • Liver / metabolism
  • Liver Cirrhosis / blood
  • Liver Cirrhosis / complications
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / etiology*
  • Male
  • Methionine / deficiency
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease / blood
  • Non-alcoholic Fatty Liver Disease / complications
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / etiology*
  • Phosphorylation / drug effects
  • Protective Agents / administration & dosage*
  • Shc Signaling Adaptor Proteins / antagonists & inhibitors*
  • Shc Signaling Adaptor Proteins / metabolism*
  • Signal Transduction / drug effects*
  • Therapeutics
  • Ubiquinone / administration & dosage
  • Ubiquinone / analogs & derivatives*


  • Protective Agents
  • Shc Signaling Adaptor Proteins
  • Ubiquinone
  • Methionine
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • idebenone