Exendin-4 restores airway mucus homeostasis through the GLP1R-PKA-PPARγ-FOXA2-phosphatase signaling.

Goblet cell hyperplasia and metaplasia and excessive mucus are prominent pathologies of chronic airway diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and chronic bronchitis. Chronic infection by respiratory pathogens, including Pseudomonas aeruginosa, exacerbates cyclical proinflammatory responses and mucus hypersecretion. P. aeruginosa and its virulence factor pyocyanin contribute to these pathologies by inhibiting FOXA2, a key transcriptional regulator of mucus homeostasis, through activation of antagonistic signaling pathways EGFR-AKT/ERK1/2 and IL-4/IL-13-STAT6-SPDEF. However, FOXA2-targeted therapy has not been previously explored. Here, we examined the feasibility of repurposing the incretin mimetic Exendin-4 to restore FOXA2-mediated airway mucus homeostasis. We have found that Exendin-4 restored FOXA2 expression, attenuated mucin production in COPD and CF-diseased airway cells, and reduced mucin and P. aeruginosa burden in mouse lungs. Mechanistically, Exendin-4 activated the GLP1R-PKA-PPAR-γ-dependent phosphatases PTEN and PTP1B, which inhibited key kinases within both EGFR and STAT6 signaling cascades. Our results may lead to the repurposing of Exendin-4 and other incretin mimetics to restore FOXA2 function and ultimately regulate excessive mucus in diseased airways.