Screening for YAP Inhibitors Identifies Statins as Modulators of Fibrosis

Am J Respir Cell Mol Biol. 2020 Apr;62(4):479-492. doi: 10.1165/rcmb.2019-0296OC.


Idiopathic pulmonary fibrosis is a lung disease with limited therapeutic options that is characterized by pathological fibroblast activation and aberrant lung remodeling with scar formation. YAP (Yes-associated protein) is a transcriptional coactivator that mediates mechanical and biochemical signals controlling fibroblast activation. In this study, we developed a high-throughput small-molecule screen for YAP inhibitors in primary human lung fibroblasts. Multiple HMG-CoA (hydroxymethylglutaryl-coenzyme A) reductase inhibitors (statins) were found to inhibit YAP nuclear localization via induction of YAP phosphorylation, cytoplasmic retention, and degradation. We further show that the mevalonate pathway regulates YAP activation, and that simvastatin treatment reduces fibrosis markers in activated human lung fibroblasts and in the bleomycin mouse model of pulmonary fibrosis. Finally, we show that simvastatin modulates YAP in vivo in mouse lung fibroblasts. Our results highlight the potential of small-molecule screens for YAP inhibitors and provide a mechanism for the antifibrotic activity of statins in idiopathic pulmonary fibrosis.

Keywords: HMG-CoA reductase inhibitor; Hippo pathway; drug screening; fibroblast; idiopathic pulmonary fibrosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl Coenzyme A / metabolism
  • Adaptor Proteins, Signal Transducing / antagonists & inhibitors*
  • Animals
  • Biomarkers / metabolism
  • Bleomycin / pharmacology
  • Cell Cycle Proteins / antagonists & inhibitors*
  • Cell Nucleus / drug effects
  • Cell Nucleus / metabolism
  • Cytoplasm / drug effects
  • Cytoplasm / metabolism
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Mevalonic Acid / metabolism
  • Mice
  • Phosphoproteins / metabolism
  • Pulmonary Fibrosis / drug therapy*
  • Pulmonary Fibrosis / metabolism
  • Signal Transduction / drug effects
  • Simvastatin / pharmacology
  • Small Molecule Libraries / pharmacology
  • YAP-Signaling Proteins


  • Acyl Coenzyme A
  • Adaptor Proteins, Signal Transducing
  • Biomarkers
  • Cell Cycle Proteins
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Phosphoproteins
  • Small Molecule Libraries
  • YAP-Signaling Proteins
  • Yap1 protein, mouse
  • Bleomycin
  • 3-hydroxy-3-methylglutaryl-coenzyme A
  • Simvastatin
  • Mevalonic Acid