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In this study, we demonstrated the protective role of hair follicle-specific epidermal growth factor receptor (EGFR) against scarring hair follicle destruction. Mechanistically, disruption of EGFR signaling generated a cell-intrinsic hypersensitivity within the JAK-STAT1 pathway, which, synergistically with interferon gamma expressing CD8 T-cell and NK-cell-mediated inflammation, compromised the stem cell niche. Hair follicle-specific genetic depletion of either JAK1\/2 or STAT1 or therapeutic inhibition of JAK1\/2 ameliorated the inflammation, restored skin barrier function and activated the residual stem cells to resume hair growth in mouse models of epidermal and hair follicle-specific EGFR deletion. Skin biopsies from EGFR inhibitor-treated and cicatricial alopecia patients revealed an active JAK-STAT1 signaling signature along with upregulation of antigen presentation and downregulation of key components of the EGFR pathway. Our findings offer molecular insights and highlight a mechanism-based therapeutic strategy for addressing chronic folliculitis associated with EGFR-inhibitor anti-cancer therapy and cicatricial alopecia.<\/jats:p>","DOI":"10.1038\/s44321-024-00166-3","type":"journal-article","created":{"date-parts":[[2024,11,9]],"date-time":"2024-11-09T05:02:40Z","timestamp":1731128560000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["JAK-STAT1 as therapeutic target for EGFR deficiency-associated inflammation and scarring alopecia"],"prefix":"10.1038","volume":"16","author":[{"given":"Karoline","family":"Strobl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00f6rg","family":"Klufa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2489-3074","authenticated-orcid":false,"given":"Regina","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4299-7542","authenticated-orcid":false,"given":"Lena","family":"Artner-Gent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7310-4340","authenticated-orcid":false,"given":"Dana","family":"Krau\u00df","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Novoszel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Strobl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1746-4250","authenticated-orcid":false,"given":"Georg","family":"Stary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3013-9823","authenticated-orcid":false,"given":"Igor","family":"Vujic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2206-9511","authenticated-orcid":false,"given":"Johannes","family":"Griss","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3362-1359","authenticated-orcid":false,"given":"Martin","family":"Holcmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0698-2992","authenticated-orcid":false,"given":"Matthias","family":"Farlik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5784-4146","authenticated-orcid":false,"given":"Bernhard","family":"Homey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6129-5613","authenticated-orcid":false,"given":"Maria","family":"Sibilia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2076-7140","authenticated-orcid":false,"given":"Thomas","family":"Bauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,11,9]]},"reference":[{"key":"166_CR1","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.immuni.2018.02.001","volume":"48","author":"J Agudo","year":"2018","unstructured":"Agudo J, Park ES, Rose SA, Alibo E, Sweeney R, Dhainaut M, Kobayashi KS, Sachidanandam R, Baccarini A, Merad M et al (2018) Quiescent tissue stem cells evade immune surveillance. 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