WFDC5 (WAP four-disulfide core domain 5) encodes a putative serine-type endopeptidase inhibitor with roles in innate immunity and mucosal defense. The protein contains WAP domains predicted to have antimicrobial activities 1, and sequence analysis suggests WFDC5 diverged early in WAP protein evolution, with distinct N-terminal and C-terminal domains serving different functions 1. WFDC5 is selectively expressed in human skin, particularly by epidermal keratinocytes as a secreted protein 2, and expression is upregulated during LPS-induced inflammation in the epididymis through NF-κB-dependent mechanisms 3, indicating region-specific roles in innate immune responses. Unlike the related protein WFDC12, WFDC5 expression is not restricted to terminal keratinocyte differentiation 4. Clinically, WFDC5 has been identified as a potential diagnostic and prognostic biomarker for melanoma metastatic progression 5 and as a smoke-responsive gene associated with esophageal squamous cell carcinoma susceptibility through gene-smoking interactions 6. These findings suggest WFDC5 contributes to cutaneous homeostasis, mucosal immunity, and potentially cancer development, though functional characterization remains incomplete.