Fig. 1

Rationale for SPLUNC1-derived peptide therapy for CF lung disease. a In normal airways, bicarbonate secretion through CFTR maintains ASL pH at ~7.0. At this pH, secreted SPLUNC1 can bind to ENaC, leading to internalization and inhibition of the channel. This helps maintain airways hydration and mucus clearance. b In CF airways, the acidic ASL, caused by a lack of bicarbonate secretion through dysfunctional CFTR, causes SPLUNC1 to adopt an inappropriate conformation, where the ENaC inhibitory domain (also known as the S18 region) cannot bind to ENaC, leading to Na⁺ hyperabsorption and ASL dehydration. c S18-derived peptides are pH-independent and can inhibit ENaC to reduce Na⁺ absorption and help normalize airway hydration/mucus clearance in acidic CF airways