WFDC2, also known as HE4 (Human epididymis protein-4), is a protein-coding gene. The WFDC2-encoded protein contains a Whey Acidic Protein domain, which is involved in the innate immune defence of multiple epithelia [5]. It has been implicated in various biological processes such as maintaining epithelial barrier integrity, and is associated with pathways related to host-microorganism interactions, immunity, and cell-cell junction regulation [2].

Recessively inherited deficiency of secreted WFDC2 causes nasal polyposis and bronchiectasis. Biallelic pathogenic variants in WFDC2 were identified in individuals from different regions. Expression of WFDC2 was detected predominantly in secretory cells of the control airway epithelium and submucosal glands, and was undetectable or hardly detectable in samples from WFDC2-deficient individuals [1]. In colonic epithelial cells, WFDC2, expressed by goblet cells, inhibits bacterial growth, preserves tight-junction integrity between epithelial cells, and prevents mucosal inflammation [2].

In ovarian cancer, HE4 (WFDC2) overexpression promotes tumor growth, chemoresistance, and creates a pro-angiogenic and immunosuppressive tumor microenvironment by regulating STAT3 target genes [6,7]. It is also overexpressed in ovarian tumors and is a potential biomarker for ovarian cancer diagnosis when combined with CA125 [3]. Additionally, WFDC2 is a candidate biomarker for early-stage lung adenocarcinoma, and its overexpression enhances the proliferation of A549 cells [4].

In conclusion, WFDC2 plays crucial roles in innate immunity, especially in maintaining the integrity of epithelial barriers in the respiratory and digestive tracts. Its dysfunction is associated with bronchiectasis, nasal polyposis, and mucosal inflammation. In cancer, WFDC2 shows potential as a biomarker and is involved in promoting tumor growth and angiogenesis, highlighting its significance in understanding disease mechanisms and developing diagnostic and therapeutic strategies.