{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T03:33:22Z","timestamp":1789788802095,"version":"4.0.1"},"reference-count":46,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T00:00:00Z","timestamp":1756944000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ERA-NET\/E-Rare-3: Joint Translational Call","award":["T3EPA-00052"],"award-info":[{"award-number":["T3EPA-00052"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Congenital ichthyoses, now grouped under the acronym EDD (Epidermal Differentiation Disorders), include nonsyndromic forms (nEDD) that may be caused by loss-of-function mutations in the CDSN gene encoding corneodesmosin (CDSN-nEDD, formerly Peeling skin syndrome type 1). It is characterized by skin peeling, inflammation, itching and food allergies, while no specific therapy is currently available. High levels of KLK5, the serine protease that initiates the desquamation cascade, are found in the epidermis of CDSN-nEDD patients. Thus, we hypothesized that KLK5 inhibition would alleviate the symptoms of CDSN-nEDD and could serve as a new pharmacological target. A human epidermal equivalent (HEE) model for CDSN-nEDD was developed using shRNA-mediated CDSN knockdown. This model was characterized and used to assess the role of KLK5 knockdown on CDSN-nEDD. Also, Klk5\u2212\/\u2212 mice were crossed with Cdsnepi\u2212\/\u2212 mice, the murine model of CDSN-nEDD, to examine in vivo the effect(s) of Klk5 deletion in CDSN-nEDD. Both models recapitulated the CDSN-nEDD desquamating phenotype. Elimination of KLK5 aggravated the CDSN-nEDD phenotype. Epidermal proteolysis was surprisingly elevated, while severe ultrastructural (corneo)desmosomal alterations increased epidermal barrier permeability and stratum corneum detachment was manifested. Based on these results, we concluded that targeting epidermal proteolysis with KLK5 ablation cannot compensate for the loss of corneodesmosin and rescue over-desquamation of the CDSN-nEDD. Possibly, in the absence of KLK5, other proteases take over which increases the severity of over-desquamation in CDSN-nEDD. The translational outcome is that over-desquamation may not always be rescued by eliminating epidermal proteolysis, but fine protease modulation is more likely required.<\/jats:p>","DOI":"10.3390\/ijms26178605","type":"journal-article","created":{"date-parts":[[2025,9,4]],"date-time":"2025-09-04T10:55:37Z","timestamp":1756983337000},"page":"8605","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Deletion of the Epidermal Protease KLK5 Aggravates the Symptoms of Congenital Ichthyosis CDSN-nEDD"],"prefix":"10.3390","volume":"26","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, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Reynier","sequence":"additional","affiliation":[{"name":"Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), CNRS, Toulouse University, Inserm, 31024 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2119-4292","authenticated-orcid":false,"given":"Georgios","family":"Pampalakis","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Health Sciences, University of Patras, Rion, 26504 Patras, Greece"},{"name":"Laboratory of Pharmacology, School of Pharmacy, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Serre","sequence":"additional","affiliation":[{"name":"Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), CNRS, Toulouse University, Inserm, 31024 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3602-0102","authenticated-orcid":false,"given":"Nathalie","family":"Jonca","sequence":"additional","affiliation":[{"name":"Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), CNRS, Toulouse University, Inserm, 31024 Toulouse, France"},{"name":"Department of Cell Biology and Cytology, Federative Institute of Biology, Purpan University Hospital, 31300 Toulouse, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgia","family":"Sotiropoulou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, School of Health Sciences, University of Patras, Rion, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1093\/bjd\/ljaf065","article-title":"Proposal for a new pathogenesis-guided classification for inherited epidermal differentiation disorders","volume":"193","author":"Paller","year":"2025","journal-title":"Br. 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