WFDC12 (WAP four-disulfide core domain 12) is a serine protease inhibitor and antibacterial protein primarily expressed in terminally differentiated keratinocytes, where it localizes to corneodesmosomes in the stratum corneum 1. The protein functions as a negative regulator of epidermal serine protease activity, specifically inhibiting neutrophil elastase and kallikrein-related peptidases 1. WFDC12 also exhibits immunomodulatory properties, reducing pro-inflammatory cytokine production (IL-8, MCP-1) in response to lipopolysaccharide stimulation 2. In disease contexts, WFDC12 overexpression exacerbates atopic dermatitis (AD) pathogenesis by enhancing arachidonic acid metabolism and platelet-activating factor accumulation while promoting Th2 immune cell infiltration 3. Conversely, WFDC12 is strongly upregulated in clinically normal-appearing skin of Netherton syndrome patients, and its expression increases following dupilumab treatment concurrent with improved epidermal barrier function 1, 4. In esophageal squamous cell carcinoma, low WFDC12 expression correlates with enhanced cell proliferation and migration, suggesting a protective role 5. WFDC12 expression is also dynamically regulated during innate immune responses in the lung and epididymis 2, 6, and is induced upon parasitic challenge 7, indicating broader roles in mucosal defense.