WFDC2 (also known as HE4) is a secreted broad-spectrum protease inhibitor with critical roles in mucosal barrier function and innate immunity. Primary function: WFDC2 is expressed by secretory epithelial cells including goblet cells and airway club cells, where it inhibits both aspartic and serine-type endopeptidases 1. Mechanism: In the intestine, WFDC2 preserves tight junction integrity, prevents bacterial invasion, and inhibits bacterial growth while dampening mucosal inflammation 1. In airways, WFDC2 is secreted into surface liquid and submucosal glands 2. Disease relevance: Biallelic WFDC2 mutations cause bronchiectasis with nasal polyposis and chr20 Pseudomonas aeruginosa infection through impaired secretion of functional protein 2. In inflammatory bowel disease, WFDC2 downregulation in goblet cells correlates with epithelial barrier breakdown 1. Conversely, WFDC2 is overexpressed in ovarian cancer and associated with reduced survival in advanced stages 3. Clinical significance: WFDC2/HE4 serves as a biomarker for ovarian cancer diagnosis with 94% specificity when combined with CA125 4. In pulmonary fibrosis, epithelial HE4 overexpression promotes aberrant epithelial-fibroblast crosstalk and myofibroblast activation, suggesting therapeutic targeting potential 5. Blood serum testing combined with genetic analysis enables diagnosis of WFDC2 deficiency 2.