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Here, this study establishes human distal lung organoids (DLOs) as a physiologically relevant model to investigate epithelial repair. Single\u2010cell transcriptomic and functional analyses identify a CD66c\n                    <jats:sup>+<\/jats:sup>\n                    basal cell subset in DLOs that resembles basal cell states enriched in idiopathic pulmonary fibrosis (IPF) lungs and exhibits inflammatory and profibrotic transcriptional programs. The data further demonstrate that secretory cells, alveolar type 2 (AT2) cells, and resident basal cells can each generate CD66c\n                    <jats:sup>+<\/jats:sup>\n                    basal cells, indicating substantial epithelial lineage plasticity. Mechanistically, the GSK3 inhibitor CHIR99021 stabilizes secretory and AT2 identities and prevents their conversion into CD66c\n                    <jats:sup>+<\/jats:sup>\n                    basal cells, accompanied by activation of ERBB4\u2010MAPK signaling. Moreover, exogenous NRG1 directly restricts this transdifferentiation through ERBB4\u2010dependent signaling, reinforcing the role of ERBB4 in maintaining epithelial lineage stability. Notably, ERBB4 expression is reduced in IPF tissues, coinciding with expansion of the CD66c\n                    <jats:sup>+<\/jats:sup>\n                    basal cell population. Together, these findings identify ERBB4 signaling as a critical regulator that constrains pathological epithelial remodeling during severe lung injury.\n                  <\/jats:p>","DOI":"10.1002\/advs.202519151","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T11:12:25Z","timestamp":1775560345000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Activation of ERBB4 Pathway Inhibits Pathological Transdifferentiation of Lung Epithelial Progenitors into CD66c\n                    <sup>+<\/sup>\n                    Basal Cells in Severe Lung Injury"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1576-0025","authenticated-orcid":false,"given":"Kaijun","family":"Lin","sequence":"first","affiliation":[{"name":"State Key Laboratory of Genetic and Development of Complex Phenotypes School of Life Sciences Zhongshan Hospital, Fudan University  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University  Shanghai China"},{"name":"Greater Bay Area Institute of Precision Medicine  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine Zhongshan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hailin","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine Zhongshan Hospital, Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery Children's Hospital Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoting","family":"Wang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic and Development of Complex Phenotypes School of Life 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinhua","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic and Development of Complex Phenotypes School of Life Sciences Zhongshan Hospital, Fudan University  Shanghai China"},{"name":"Greater Bay Area Institute of Precision Medicine  Guangzhou China"},{"name":"State Key Laboratory of Reproductive Regulation and Breeding of Grassland Livestock Institutes of Biomedical Sciences School of Life Sciences Inner Mongolia University  Hohhot China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shenfei","family":"Sun","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Genetic and Development of Complex Phenotypes School of Life Sciences Zhongshan Hospital, Fudan University  Shanghai China"},{"name":"Greater Bay Area Institute of Precision Medicine  Guangzhou China"},{"name":"State Key Laboratory of Reproductive Regulation and Breeding of 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