Fatty acid synthase inhibition alleviates lung fibrosis via β-catenin signal in fibroblasts

Idiopathic pulmonary fibrosis is a progressive and lethal interstitial lung disease with an unclear etiology and limited treatment options. Fatty acid synthase (FASN) plays various roles in metabolic-related diseases. This study demonstrates that FASN expression is increased in fibroblasts from the lung tissues of patients with idiopathic pulmonary fibrosis and in bleomycin-treated mice. In MRC-5 cells, the inhibition of FASN using shRNA or the pharmacological inhibitor C75 resulted in the increased mRNA and protein expression of glycogen synthase kinase 3 beta and Axin1, both negative regulators of the Wnt/beta-catenin signaling pathway, and promoted autophagy. This outcome led to a decrease in beta-catenin protein and mRNA levels, effectively inhibiting the proliferation, migration, and differentiation of lung fibroblasts into myofibroblasts, while inducing the differentiation of fibroblasts into adipofibroblasts. In vivo experiments showed that C75 alleviated bleomycin-induced lung fibrosis in mice by inhibiting beta-catenin. In conclusion, these findings suggest that inhibiting FASN in fibroblasts may diminish the activity of the Wnt/beta-catenin signaling pathway, providing a potential therapeutic avenue for pulmonary fibrosis.