Pharmacologic CFTR potentiation attenuates alveolar epithelial senescence and experimental pulmonary fibrosis

Abstract Idiopathic pulmonary fibrosis (IPF) is a deadly lung disease that urgently requires effective treatments. A major factor driving IPF is the aging of alveolar type 2 (AT2) cells, which disrupts epithelial homeostasis and promotes fibrotic remodeling. Lungs from IPF patients exhibit reduced expression of the cystic fibrosis transmembrane conductance regulator (CFTR), particularly in AT2 cells, which typically have high CFTR levels. It remains unclear whether acquired CFTR dysfunction contributes to the development of IPF. This study examines whether the CFTR potentiator VX-770 (ivacaftor) can reduce experimental pulmonary fibrosis by targeting AT2 cell senescence. In a bleomycin-induced pulmonary fibrosis mouse model, VX-770 treatment reduced pulmonary fibrosis by limiting collagen deposition and restoring normal lung structure and function. The treatment reestablished epithelial homeostasis, decreasing aberrant KRT8 + transitional cells and preventing the loss of alveolar type 1 cells. Notably, VX-770 diminished cellular senescence both in vivo and in AT2 cell organoid cultures by decreasing the expression of senescence markers and the pro-fibrotic senescence-associated secretory phenotype. Notably, deleting CFTR specifically in AT2 cells lessened the therapeutic effect of VX-770, confirming its target-specific action. Mechanistically, VX-770 stabilized the CFTR-PTEN protein complex, elevating PTEN levels and thereby inhibiting the profibrotic PI3K/AKT signaling pathway. Overall, these findings identify acquired CFTR dysfunction as a key druggable driver of pulmonary fibrosis, providing preclinical evidence supporting the repurposing of VX-770 as a novel senescence-targeting therapy for IPF.