Evaluation of NV556, a Novel Cyclophilin Inhibitor, as a Potential Antifibrotic Compound for Liver Fibrosis

Cells. 2019 Nov 8;8(11):1409. doi: 10.3390/cells8111409.


Hepatic fibrosis can result as a pathological response to nonalcoholic steatohepatitis (NASH). Cirrhosis, the late stage of fibrosis, has been linked to poor survival and an increased risk of developing hepatocellular carcinoma, with limited treatment options available. Therefore, there is an unmet need for novel effective antifibrotic compounds. Cyclophilins are peptidyl-prolyl cis-trans isomerases that facilitate protein folding and conformational changes affecting the function of the targeted proteins. Due to their activity, cyclophilins have been presented as key factors in several stages of the fibrotic process. In this study, we investigated the antifibrotic effects of NV556, a novel potent sanglifehrin-based cyclophilin inhibitor, in vitro and in vivo. NV556 potential antifibrotic effect was evaluated in two well-established animal models of NASH, STAM, and methionine-choline-deficient (MCD) mice, as well as in an in vitro 3D human liver ECM culture of LX2 cells, a human hepatic stellate cell line. We demonstrate that NV556 decreased liver fibrosis in both STAM and MCD in vivo models and decreased collagen production in TGFβ1-activated hepatic stellate cells in vitro. Taken together, these results present NV556 as a potential candidate for the treatment of liver fibrosis.

Keywords: 3D in vitro model; NV556; STAM; cyclophilin; decellularized human liver; hepatic stellate cells (HSC); liver fibrosis; methionine-choline-deficient (MCD) diet; nonalcoholic steatohepatitis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Choline Deficiency
  • Collagen Type I / metabolism
  • Cyclophilins / antagonists & inhibitors*
  • Diet
  • Disease Models, Animal
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Humans
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Male
  • Methionine / deficiency
  • Mice
  • Molecular Targeted Therapy
  • Non-alcoholic Fatty Liver Disease / drug therapy
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology


  • Collagen Type I
  • Methionine
  • Cyclophilins