Inhibition of fatty acid synthase in fibroblasts alleviates pulmonary fibrosis through the regulation of β- catenin

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease with poor therapeutic options while the pathogenesis keeps elusive. Herein we demonstrated that the expression of FASN was increased in fibroblasts of IPF and bleomycin-induced mouse lungs, and both TGF-β1 and overexpression of β-catenin promoted the protein and mRNA expression of FASN. In MRC-5 cells, inhibition of FASN with FASN shRNA or pharmacological inhibitor C75 restrained the proliferation and the migration of the fibroblasts, and reduced the transformation of lung fibroblasts into myofibroblasts. In addition, inhibition of FASN reduced the total protein and mRNA level of β-catenin, further decreased the protein content of β-catenin in the cytoplasm and the nucleus. These effects keep the fibroblasts in a quiescent state and contribute to the treatment of IPF. Mechanistic studies showed inhibition of FASN increased negative regulators of β-catenin including glycogen synthase kinase 3β (GSK3B) and Axin1 through FASN interaction with GSK3B and Axin1. Animal studies shown that inhibition of FASN by pharmacological inhibitor C75 alleviated bleomycin-induced pulmonary fibrosis in mice. Therefore, these results suggested that inhibition of FASN in fibroblast reduced the activity of the Wnt/β-catenin signaling pathway, effectively alleviated pulmonary fibrosis. Inhibition of FASN in fibroblasts will be a potential approach for the treatment of pulmonary fibrosis.