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We previously reported the in\u00a0vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in\u00a0vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. The cell-autonomous AEC2 reprogramming can be attenuated through inhibition of inositol-requiring enzyme 1 (IRE1\u03b1) signaling as the use of an IRE1\u03b1 inhibitor reduced the development of the reprogrammed cell state and also diminished AEC2-driven recruitment of granulocytes, alveolitis, and lung injury. These findings identify AEC2 proteostasis, and specifically IRE1\u03b1 signaling through its major product XBP-1, as a driver of a key AEC2 phenotypic change that has been identified in lung fibrosis.<\/jats:p>","DOI":"10.1073\/pnas.2123187119","type":"journal-article","created":{"date-parts":[[2022,10,17]],"date-time":"2022-10-17T15:10:57Z","timestamp":1666019457000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":37,"title":["Disruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9208-7729","authenticated-orcid":false,"given":"Jeremy","family":"Katzen","sequence":"first","affiliation":[{"name":"Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pennsylvania, Philadelphia, 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