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Dysregulated epidermal protease activity results in impaired skin barrier function and chronic inflammation, accompanied by complex immune profiles. NS patients commonly show activation of the inflammatory axis, centered on IL\u201017 and IL\u201036, in the skin and blood, and show a psoriasis\u2010like shift to Th17. Conversely, the immune profile differs depending on the clinical type, with ichthyosis linearis circumflexa type characterized by complement activation and Th2\u2010type allergic responses, and scaly erythroderma type characterized by a type I IFN signature and Th9\u2010type allergic responses. While symptomatic treatments such as emollients and topical corticosteroids have been the mainstay of care, recent advances have opened new therapeutic avenues involving biologic agents and oral small\u2010molecule immunomodulators. This review provides a comprehensive overview of the current clinical landscape and future directions of biologics (e.g., dupilumab, secukinumab, ustekinumab) and small\u2010molecule therapies (e.g., JAK inhibitors such as tofacitinib, baricitinib, and upadacitinib) in the treatment of NS. Though evidence remains limited to case reports and small series, preliminary data suggest that cytokine\u2010targeted interventions\u2014particularly those inhibiting IL\u20104, IL\u201013, IL\u201017, IL\u201036, and JAK pathways\u2014may offer tangible clinical benefits. Well\u2010designed clinical trials and mechanistic investigations are crucial to establishing their place in NS management.<\/jats:p>","DOI":"10.1111\/1346-8138.17923","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T10:58:32Z","timestamp":1756724312000},"page":"1483-1493","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Biologics and Small\u2010Molecule Therapies in Netherton Syndrome: A Comprehensive Review"],"prefix":"10.1111","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1374-065X","authenticated-orcid":false,"given":"Shin","family":"Morizane","sequence":"first","affiliation":[{"name":"Department of Dermatology Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences  Okayama 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