SPINK6 (serine peptidase inhibitor Kazal type 6) is a selective serine protease inhibitor that functions primarily as a tissue-specific regulator of kallikrein-related peptidases (KLKs). It efficiently inhibits multiple KLK family members including KLK4, KLK5, KLK6, KLK7, KLK12, KLK13, and KLK14, but does not inhibit KLK8 1. The protein contains a single Kazal domain with three critical intramolecular disulfide bonds required for proper folding and inhibitory activity 2. SPINK6 expression is prominent in the stratum granulosum of human skin and in skin appendages, where it regulates KLK-mediated desquamation 1. In the airway, SPINK6 restricts influenza A virus activation by inhibiting serine proteases HAT and KLK5, which are required for hemagglutinin cleavage and viral replication 3. Individuals carrying higher SPINK6 expression alleles show protection from H7N9 infection 3. Beyond protective roles, SPINK6 exhibits pathological involvement in cancer progression. In hepatocellular carcinoma, the BAP31-ELAVL1-SPINK6 axis promotes metastasis through loss of cell polarity and epithelial-mesenchymal transition 4. Similarly, SPINK6 activation of the EGFR/EphA2 complex drives melanoma metastasis 5. SPINK6 expression is reduced in atopic dermatitis lesions and downregulated following skin barrier disruption, suggesting its importance in maintaining epidermal integrity 16.