Screening for YAP Inhibitors Identifies Statins as Modulators of Fibrosis.

In this study, we developed a high-throughput small molecule screen for YAP inhibitors in primary human lung fibroblasts (HLF). Multiple hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) 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 HLF and in the bleomycin mouse model of pulmonary fibrosis. Finally, we show 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 anti-fibrotic activity of statins in IPF.
PMID: 31944822 [PubMed - as supplied by publisher]

Source: American Journal of Respiratory Cell and Molecular Biology - January 15, 2020 Category: Molecular Biology Authors: Santos DM, Pantano L, Pronzati G, Grasberger P, Probst CK, Black KE, Spinney JJ, Hariri LP, Nichols R, Lin Y, Bieler M, Seither P, Nicklin P, Wyatt D, Tager AM, Medoff BD Tags: Am J Respir Cell Mol Biol Source Type: research