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Histone lysine demethylase 6B (KDM6B) may either prevent or promote organ fibrosis, but its specific role in IPF is yet to be clarified. This study aimed to investigate the function and mechanisms of KDM6B in IPF and the exacerbating effects of OSA. We assessed KDM6B levels in lung tissues from IPF patients, IPF mouse models, and a dual\u2010hit model combining OSA\u2010associated intermittent hypoxia (IH) with bleomycin (BLM) or TGF\u2010\u03b21. We evaluated pulmonary fibrosis, myofibroblast activation, and oxidative stress. KDM6B levels were elevated in lung tissues from IPF patients and BLM\u2010treated mice, as well as in TGF\u2010\u03b21\u2010stimulated myofibroblasts. Importantly, IH significantly worsened BLM\u2010induced pulmonary fibrosis and TGF\u2010\u03b21\u2010induced myofibroblast activation, further amplifying KDM6B expression both in\u00a0vivo and in\u00a0vitro. Inhibition of KDM6B reduced pulmonary fibrosis and decreased fibroblast activation and migration in IPF and dual\u2010hit models. Mechanistically, KDM6B inhibition led to decreased NOX4 expression and reduced oxidative stress. KDM6B plays a critical role in promoting pulmonary fibrosis and mediating the exacerbating effects of OSA on this condition. Our findings identify KDM6B as a novel potential therapeutic target for IPF.<\/jats:p>","DOI":"10.1096\/fj.202402813r","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T04:16:31Z","timestamp":1736396191000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The histone demethylase KDM6B links obstructive sleep apnea to idiopathic pulmonary fibrosis"],"prefix":"10.1096","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3012-6459","authenticated-orcid":false,"given":"Shuangyu","family":"Han","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine Tianjin Medical University General Hospital  Tianjin China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-4279-2914","authenticated-orcid":false,"given":"Jie","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of 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