SPINK9 (serine peptidase inhibitor Kazal type 9) is a skin-specific Kazal-type serine protease inhibitor with dual functions in cutaneous homeostasis and innate immunity. Primary function: SPINK9 selectively inhibits kallikrein-related peptidase 5 (KLK5) with high specificity (Ki ~65 nM), playing a regulatory role in skin desquamation 1. The inhibitor is predominantly expressed in palmo-plantar epidermis, particularly in the stratum corneum and stratum granulosum 2. Mechanism: SPINK9's reactive loop (residues 48-49) inserts into KLK5's binding pocket with pH-dependent efficiency, explaining enhanced inhibition at physiological skin pH 3. Beyond protease inhibition, SPINK9 functions as an antimicrobial peptide, selectively killing Escherichia coli through intracellular interactions with bacterial chaperone SKP 4. SPINK9 also stimulates keratinocyte migration via purinergic receptor-mediated EGFR transactivation and metalloprotease activation 5. Disease relevance: SPINK9 is significantly upregulated in type 1 diabetes complications including neuropathy and ketoacidosis 6, and identified as a prognostic gene in non-smoking head and neck squamous cell carcinoma 7. Clinical significance: SPINK9 represents a multifunctional epidermal peptide maintaining both physical and immunological skin barriers.