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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\u2010of\u2010function mutations in the\n                    <jats:italic>SPINK5<\/jats:italic>\n                    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.\n                    <jats:italic>Spink5<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice recapitulate the major features of the human disease but exhibit neonatal lethality. Several double\u2010 and triple\u2010knockout 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\u2010deficient epidermis can reverse the cutaneous manifestations of NS. In particular, ablation of KLK5 results in a marked therapeutic response, although KLK7 or TNF\u03b1 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\n                    <jats:italic>in vitro<\/jats:italic>\n                    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\u2010specific candidate therapeutics can be tested and preclinically validated. \u00a9 2026 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70018","type":"journal-article","created":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T17:20:29Z","timestamp":1767979229000},"page":"249-262","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dysregulated proteolytic cascades in Netherton syndrome: from molecular pathology to preclinical drug testing"],"prefix":"10.1002","volume":"268","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5387-0470","authenticated-orcid":false,"given":"Eleni","family":"Zingkou","sequence":"first","affiliation":[{"name":"Department of Pharmacy, School of Health Sciences University of Patras  Rion\u2010Patras Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evangelos","family":"Bisyris","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Health Sciences University of Patras  Rion\u2010Patras Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2119-4292","authenticated-orcid":false,"given":"Georgios","family":"Pampalakis","sequence":"additional","affiliation":[{"name":"Laboratory of Pharmacology, School of Pharmacy Aristotle University of Thessaloniki  Thessaloniki Greece"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0747-4914","authenticated-orcid":false,"given":"Georgia","family":"Sotiropoulou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Health Sciences University of Patras  Rion\u2010Patras 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