Statins Used to Lower Cholesterol May Be Treatment for IPF, Study Suggests

Statins, a class of medications widely prescribed to lower cholesterol levels and prevent heart disease and stroke, may be an effective treatment for  idiopathic pulmonary fibrosis (IPF), a study suggests.

The study, “Screening for YAP Inhibitors Identifies Statins as Modulators of Fibrosis,” was published recently in the journal American Journal of Respiratory Cell and Molecular Biology.

Nintedanib (sold as Ofev by Boehringer Ingelheim) and pirfenidone (sold as Esbriet by Genentech) have been approved to treat IPF, but do not stop or reverse the disease’s progression.

When active, proteins called Yes Associated Protein (YAP) and Transcriptional co-Activator with PDZ-binding motif (TAZ) enter the cell nucleus, where genetic information is stored, to activate genes controlling cell growth, survival, and migration.

YAP/TAZ control several signaling pathways involved in fibrosis, or tissue scarring, as shown in several studies of the tissue cells promoting fibrosis, called fibroblasts.

It also has been shown that fibroblasts in IPF patients’ lungs have higher levels of YAP/TAZ in the nucleus, and reduction in levels of both proteins impairs their ability to form scar tissue.

Inhibiting YAP/TAZ and blocking fibroblasts’ pro-fibrotic activity may be potential therapies for IPF.

Researchers at Boehringer Ingelheim, Harvard Medical School, and Harvard T. H. Chan School of Public Health performed a high-throughput, small molecule screen for YAP inhibitors in human lung fibroblasts.

After screening 13,232 compounds, they discovered different types of small molecules that can block YAP activity and found that several statins — including simvastatin, cerivastatin, mevastatin, lovastatin, fluvastatin, pitavastatin, and atorvastatin — were strong inhibitors of YAP.

To confirm these findings, investigators performed several experiments with statins on lung fibroblasts derived from both IPF patients and healthy donors. In both cases, statins — namely simvastatin and mevastatin — reduced YAP levels in the cells’ nucleus in a dose-dependent manner.

The team found that statins can reduce the levels of YAP by promoting its phosphorylation (addition of a phosphate group) and marking the protein for degradation (elimination).

Previous studies in other cell types showed that statins regulate YAP through the mevalonate pathway, which is responsible for producing cholesterol. Researchers now have observed that in human lung fibroblasts, statins can control YAP activity by modulating the same pathway.

Finally, researchers tested the effects of simvastatin in vivo, using a mouse model of induced pulmonary fibrosis. They found that simvastatin reduced the accumulation of collagen (one of the proteins produced by fibroblasts) in the animals’ lungs, as well as lowered fibrosis markers and tissue remodeling triggered by fibrosis.

“Here, we present the novel finding that the antifibrotic effects of statins in the lung are mediated at least in part through YAP modulation in lung fibroblasts. Whether statins modulate YAP activity in other in vivo fibrosis models in different organs remains to be investigated,” researchers wrote.

Because statins are safe and commonly prescribed, they hold appeal as a treatment for IPF. Results are promising, but prospective studies are needed to determine effects of statin therapy in patients with IPF.

“Our work provides a likely antifibrotic mechanism for statins in IPF, contributing to the body of evidence that warrants further studies into the clinical potential of statins in IPF and other fibrotic diseases,” the researchers stated.