SPINK5 encodes lymphoepithelial Kazal-type-related inhibitor (LEKTI), a serine protease inhibitor essential for skin barrier function and immune homeostasis. LEKTI regulates activity of kallikrein-related proteases (KLKs), particularly KLK5, in a pH-dependent manner, and inhibits additional proteases including KLK7, KLK14, caspase-14, and trypsin 1. This inhibitory function maintains skin integrity by controlling desquamation-involved and defense-activating proteases while contributing to anti-inflammatory and antimicrobial protection of epithelial surfaces 2. Loss-of-function SPINK5 mutations cause Netherton syndrome (NS), the most common syndromic epidermal differentiation disorder 3. NS pathogenesis involves uncontrolled protease activity, leading to compromised skin barrier function, elevated serum IgE levels, and systemic inflammation characterized by upregulated IL-17, IL-36, and IL-20 signaling 2. Proteolytic dysregulation activates the KLK/IL-36 axis, driving inflammation independent of primary T cell immunodeficiency 2. SPINK5 polymorphisms also associate with atopic dermatitis susceptibility across populations 4. Beyond dermatological manifestations, SPINK5 deficiency predisposes to severe HPV-related anogenital lesions and requires immunodeficiency screening in extensive warts 5. Emerging therapeutics targeting this pathway include kallikrein inhibitors and TNF-α inhibitors, offering pathogenesis-based treatment approaches 3, 6.