Dysregulated proteolytic cascades in Netherton syndrome: from molecular pathology to preclinical drug testing

Netherton syndrome (NS) is a rare, severe, and often life-threatening disease for which current therapeutic approaches are limited and show variable effectiveness. NS is characterized by excessive epidermal desquamation that results in a highly defective epidermal barrier, constitutive skin inflammation, allergies, and hair abnormalities. NS develops due to loss-of-function mutations in the SPINK5 gene, which encodes the LEKTI inhibitor that regulates KLK proteases (KLK5, KLK6, KLK7, KLK13, and KLK14). These findings indicate that dysregulation of proteolytic networks underlies the extensive skin shedding and inflammation characteristic of NS. Spink5^-/- mice recapitulate the major features of the human disease but exhibit neonatal lethality. Several double- and triple-knockout models have been generated to rescue the lethal NS phenotype, and have proved instrumental in studies aiming to elucidate the biological pathways involved in NS, and to identify and validate potential targets for drug development. These studies have established that inhibition of excessive KLK protease activity in LEKTI-deficient epidermis can reverse the cutaneous manifestations of NS. In particular, ablation of KLK5 results in a marked therapeutic response, although KLK7 or TNFα must also be inhibited to rescue the most severe (lethal) form of NS. Murine models have also been essential in proving or disproving putative pathways and/or therapeutic targets proposed from in vitro studies or patient case studies. Collectively, these models have provided a deeper understanding of the epidermal proteolytic cascades involved in NS pathology and in normal skin renewal. Moreover, these models offer a platform in which disease-specific candidate therapeutics can be tested and preclinically validated. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.