{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T21:51:27Z","timestamp":1781905887205,"version":"3.54.5"},"reference-count":35,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T00:00:00Z","timestamp":1741910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Susan Cheney Scleroderma","award":["BB\/S01716X\/1"],"award-info":[{"award-number":["BB\/S01716X\/1"]}]},{"name":"Susan Cheney Scleroderma","award":["BB\/W018640\/1"],"award-info":[{"award-number":["BB\/W018640\/1"]}]},{"name":"Discovery Medicine North (DiMeN) Medical Research Council","award":["BB\/S01716X\/1"],"award-info":[{"award-number":["BB\/S01716X\/1"]}]},{"name":"Discovery Medicine North (DiMeN) Medical Research Council","award":["BB\/W018640\/1"],"award-info":[{"award-number":["BB\/W018640\/1"]}]},{"name":"National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC)","award":["BB\/S01716X\/1"],"award-info":[{"award-number":["BB\/S01716X\/1"]}]},{"name":"National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC)","award":["BB\/W018640\/1"],"award-info":[{"award-number":["BB\/W018640\/1"]}]},{"name":"Biotechnology and Biological Sciences Research Council (BBSRC)","award":["BB\/S01716X\/1"],"award-info":[{"award-number":["BB\/S01716X\/1"]}]},{"name":"Biotechnology and Biological Sciences Research Council (BBSRC)","award":["BB\/W018640\/1"],"award-info":[{"award-number":["BB\/W018640\/1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Systemic sclerosis (SSc) is an autoimmune disease of unknown aetiology characterised by vasculopathy with progressive fibrosis of the skin and internal organs. Tissue fibrosis is driven by activated fibroblasts (myofibroblasts) with exacerbated contractile and secretory properties. We previously reported that the long non-coding RNA HOTAIR is a key driver of SSc fibroblast activation. HOTAIR interacts with the chromatin modifiers, the polycomb repressor complex (PRC2) and coREST complex, promoting expression of pro-fibrotic genes. In this study, we show that acute activation of dermal fibroblasts from healthy subjects or SSc patients with transforming growth factor-\u03b2 and other fibrotic stimuli requires the activity of the lysine-specific demethylase 1 (LSD1) subunit of the co-REST complex. Unexpectedly, LSD1 catalytic activity plays a minor role in fibrotic gene expression in HOTAIR-overexpressing fibroblasts and in maintenance of the stable myofibroblast phenotype of SSc fibroblasts. However, silencing of LSD1 in SSc fibroblasts has a profound effect on pro-fibrotic gene expression, supporting a non-canonical scaffolding function. Our study shows for the first time an essential non-canonical role for LSD1 in pro-fibrotic gene expression in SSc; however, given that this function is insensitive to LSD1 inhibitors, the therapeutic opportunities will depend on future identification of a targetable mediator.<\/jats:p>","DOI":"10.3390\/cells14060433","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T04:29:18Z","timestamp":1741926558000},"page":"433","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Lysine Demethylase 1 Has Demethylase-Dependent and Non-Canonical Functions in Myofibroblast Activation in Systemic Sclerosis"],"prefix":"10.3390","volume":"14","author":[{"given":"Christopher W.","family":"Wasson","sequence":"first","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1218-4399","authenticated-orcid":false,"given":"Esther","family":"Perez Barreiro","sequence":"additional","affiliation":[{"name":"School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8528-2283","authenticated-orcid":false,"given":"Francesco","family":"Del Galdo","sequence":"additional","affiliation":[{"name":"Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK"},{"name":"Scleroderma Programme, NIHR Leeds Musculoskeletal Biomedical Research Centre, Leeds LS7 4SA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8942-7873","authenticated-orcid":false,"given":"Natalia A.","family":"Riobo-Del Galdo","sequence":"additional","affiliation":[{"name":"School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK"},{"name":"Leeds Institute of Medical Research, Faculty of Medicine and Health, University of Leeds, Leeds LS2 9JT, UK"},{"name":"Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1172\/JCI31139","article-title":"Systemic sclerosis: A prototypic multisystem fibrotic disorder","volume":"117","author":"Varga","year":"2007","journal-title":"J. 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