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However, the mechanisms driving immune-mediated fibrosis remain poorly understood. In this study, we combined molecular biology approaches with spatial transcriptomics in ex vivo patient samples and in vitro models to characterize a novel loss-of-function ISG15 variant and to elucidate disease-associated molecular pathways. Analysis of patient skin biopsies revealed increased IFN-I\u2013dependent apoptosis, altered macrophage polarization, enhanced epithelial-to-mesenchymal transition (EMT), and myofibroblast activation. In vitro, ISG15 knockout (KO), but not wild-type (WT), epithelial cells were predisposed to EMT following combined TGF-\u03b2 and IFN-I stimulation. Additionally, ISG15 KO fibroblasts displayed impaired mechanical wound healing and increased IFN-I\u2013induced apoptosis compared with WT cells. Collectively, our findings suggest that chronic IFN-I exposure in ISG15 deficiency disrupts wound repair, skews macrophage activation, and promotes EMT, contributing to fibrosis across multiple organ systems.<\/jats:p>","DOI":"10.70962\/jhi.20250011","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T07:21:41Z","timestamp":1769152901000},"update-policy":"https:\/\/doi.org\/10.70962\/jhi.crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Human ISG15 deficiency unveils impaired healing of ulcerations via type I interferon\u2013mediated fibrosis"],"prefix":"10.70962","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0999-3091","authenticated-orcid":true,"given":"Christos","family":"Sazeides","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00hj8s172","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Genetic Errors of Immunity, Columbia University 1 , New York, 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