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Nudix Hydrolase 21 (NUDT2 or CFIm25) downregulation in fibroblasts is known to play detrimental roles in both skin and lung fibrosis. This study aims to investigate the upstream mechanisms that lead to NUDT21 repression in skin fibrosis. We identified transforming growth factor \u03b2 (TGF\u03b21) as the primary cytokine that downregulated NUDT21 in normal skin fibroblasts. In the bleomycin\u2010induced dermal fibrosis model, consistent with the peak activation of TGF\u03b21 at the late fibrotic stage, NUDT21 was downregulated at this stage, and delayed NUDT21 knockdown during this fibrotic phase led to enhanced fibrotic response to bleomycin. Further investigation suggested TGF\u03b2 downregulated NUDT21 through microRNA (miRNA) 181a and 181b induction. Both miR\u2010181a and miR\u2010181b were elevated in bleomycin\u2010induced skin fibrosis in mice and primary fibroblasts isolated from SSc patients, and they directly targeted NUDT21 and led to its downregulation in skin fibroblasts. Functional studies demonstrated that miR\u2010181a and miR\u2010181b inhibitors attenuated bleomycin\u2010induced skin fibrosis in mice in association with decreased NUDT21 expression, while miR\u2010181a and miR\u2010181b mimics promoted bleomycin\u2010induced fibrosis. Overall, these findings suggest a novel role for miR\u2010181a\/b in SSc pathogenesis by repressing NUDT21 expression.<\/jats:p>","DOI":"10.1096\/fj.202400829r","type":"journal-article","created":{"date-parts":[[2024,9,9]],"date-time":"2024-09-09T12:10:29Z","timestamp":1725883829000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Unraveling the role of\n                    <scp>MiR<\/scp>\n                    \u2010181 in skin fibrosis pathogenesis by targeting\n                    <scp>NUDT21<\/scp>"],"prefix":"10.1096","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6041-4788","authenticated-orcid":false,"given":"Tingting W.","family":"Mills","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Biology The University of Texas Health Science Center at Houston  Houston Texas 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Houston  Houston Texas USA"},{"name":"Department of Internal Medicine, Division of Rheumatology The University of Texas Health Science Center at Houston  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio","family":"Charles","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Rheumatology The University of Texas Health Science Center at Houston  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology The University of Texas Health Science Center at Houston  Houston Texas USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung\u2010hee","family":"Yoo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology The University of Texas Health Science Center at Houston  Houston Texas 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