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DATPs express profibrotic genes, suggesting that they might promote idiopathic pulmonary fibrosis (IPF). However, the molecular pathways that induce and\/or maintain DATPs are incompletely understood. Here we show that the bifunctional kinase\/RNase\u2014IRE1\u03b1\u2014a central mediator of the unfolded protein response (UPR) to endoplasmic reticulum (ER) stress is a critical promoter of DATP abundance and function. Administration of a nanomolar-potent, monoselective kinase inhibitor of IRE1\u03b1 (KIRA8)\u2014or conditional epithelial IRE1\u03b1 gene knockout\u2014both reduce DATP cell number and fibrosis in the bleomycin model, indicating that IRE1\u03b1 cell-autonomously promotes transition into the DATP state. IRE1\u03b1 enhances the profibrotic phenotype of DATPs since KIRA8 decreases expression of integrin \u03b1v\u03b26, a key activator of transforming growth factor \u03b2 (TGF-\u03b2) in pulmonary fibrosis, corresponding to decreased TGF-\u03b2-induced gene expression in the epithelium and decreased collagen accumulation around DATPs. Furthermore, IRE1\u03b1 regulates DNA damage response (DDR) signaling, previously shown to promote the DATP phenotype, as IRE1\u03b1 loss-of-function decreases H2AX phosphorylation, Cdkn1a (p21) expression, and DDR-associated secretory gene expression. Finally, KIRA8 treatment increases the differentiation of Krt19\n                    <jats:sup>CreERT2<\/jats:sup>\n                    -lineage-traced DATPs into type 1 alveolar epithelial cells after bleomycin injury, indicating that relief from IRE1\u03b1 signaling enables DATPs to exit the transitional state. Thus, IRE1\u03b1 coordinates a network of stress pathways that conspire to entrap injured cells in the DATP state. Pharmacological blockade of IRE1\u03b1 signaling helps resolve the DATP state, thereby ameliorating fibrosis and promoting salutary lung regeneration.\n                  <\/jats:p>","DOI":"10.1152\/ajplung.00408.2021","type":"journal-article","created":{"date-parts":[[2022,2,16]],"date-time":"2022-02-16T08:01:07Z","timestamp":1644998467000},"page":"L564-L580","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":37,"title":["IRE1\u03b1 drives lung epithelial progenitor dysfunction to establish a niche for pulmonary fibrosis"],"prefix":"10.1152","volume":"322","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6273-1595","authenticated-orcid":true,"given":"Vincent C.","family":"Auyeung","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California, San Francisco, California"},{"name":"Lung Biology Center, University of California, San 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California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Sheppard","sequence":"additional","affiliation":[{"name":"Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Department of Medicine, University of California, San Francisco, California"},{"name":"Lung Biology Center, University of California, San Francisco, California"},{"name":"Department of Medicine, University of California, San Francisco, California"},{"name":"Cardiovascular Research Institute, University of California, San Francisco, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3684-9108","authenticated-orcid":true,"given":"Feroz R.","family":"Papa","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco, California"},{"name":"Diabetes Center, University of California, San Francisco, California"},{"name":"Quantitative Biosciences Institute, University of 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