Elexacaftor/Tezacaftor/Ivacaftor Reshapes Airway Inflammation and Proteomic Landscape in Cystic Fibrosis

BackgroundElexacaftor/Tezacaftor/Ivacaftor (ETI) has significantly improved clinical outcomes for people with cystic fibrosis (pwCF), but the molecular effects on airway inflammation remains incompletely understood. This study aimed to characterise longitudinal changes in airway inflammation and sputum proteomes following ETI treatment, and to correlate proteomic shifts to changes in inflammatory cytokines. Patients and methodsSputum from pwCF (n=30) were collected before start of ETI and after 3 and 9-12 months of treatment. Sputum from healthy control subjects (n=7) were included for comparison. Samples were analysed for total proteome content using data independent acquisition liquid chromatography tandem mass spectrometry (DIA LC-MS/MS), and inflammatory cytokines using Mesoscale assays. Protein expression trends were analysed using k-means clustering, and correlations between airway proteomes and inflammatory cytokines were performed using Pearson correlation and enrichment analysis. ResultsETI therapy resulted in significant changes in the airway proteome, mainly related to decreased neutrophil degranulation and an increase in anti-proteases. Levels of IL-1{beta}, IL-8, and TNF decreased with ETI therapy, which correlated with proteins involved in neutrophil degranulation. In contrast, IL-6 levels increased and correlated with proteins involved in O-glycosylation of mucins. Despite these improvements, proteomic and cytokine profiles remained distinct from healthy controls after 9-12 months. ConclusionETI leads to broad shifts in airway protein expression in pwCF with reduced neutrophilic inflammation and restored protease/antiprotease balance. Despite these changes, there is still increased airway inflammation compared to healthy control sputum. This dataset provides a valuable resource for further exploration of CF airway biology under ETI therapy.