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To elucidate the pathogenesis of CLAD, we conducted a comprehensive single-cell transcriptomic analysis of CLAD lungs, integrating our generated datasets with approximately 1.6 million cells from 15 published studies of other fibrotic lung diseases. By applying pseudo-bulk approaches to mitigate batch effects, we identified molecular signatures specific to CLAD and those shared with idiopathic pulmonary fibrosis, COVID-19, and other fibrotic conditions. Our analysis revealed CLAD-specific cellular subsets including Fibro.AT2 cells, exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, and superactivated macrophages while suggesting that pathogenic keratin 17\u2013positive, keratin 5\u2013negative (KRT17\n                    <jats:sup>+<\/jats:sup>\n                    KRT5\n                    <jats:sup>\u2212<\/jats:sup>\n                    ) cells represent a common fibrotic mechanism across fibrotic lung diseases. Additionally, we performed donor-recipient cell deconvolution in lung allografts, uncovering distinct transcriptional programs and intercellular crosstalk between donor- and recipient-derived cells that drive allograft fibrosis. Recipient-derived stromal and immune cells showed enhanced pro-fibrotic and allograft rejection pathways compared with their donor counterparts. By leveraging insights from other fibrotic diseases to elucidate CLAD-specific mechanisms, our study provides a molecular framework for understanding CLAD pathogenesis and identifies potential therapeutic targets for this treatment-refractory condition.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.197579","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T18:00:42Z","timestamp":1761069642000},"source":"Crossref","is-referenced-by-count":16,"title":["Single-cell dissection of chronic lung allograft dysfunction reveals convergent and distinct fibrotic mechanisms"],"prefix":"10.1172","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0094-7726","authenticated-orcid":true,"given":"Yuanqing","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Surgery, Division of Thoracic Surgery;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taisuke","family":"Kaihou","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Thoracic Surgery;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4387-1386","authenticated-orcid":true,"given":"Emilia","family":"Lecuona","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Thoracic Surgery;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Thoracic Surgery;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7767-6584","authenticated-orcid":true,"given":"Masahiko","family":"Shigemura","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Thoracic Surgery;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiying","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Thoracic Surgery;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chitaru","family":"Kurihara","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Thoracic Surgery;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruli","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2857-1441","authenticated-orcid":true,"given":"Felix L.","family":"Nunez-Santana","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Thoracic Surgery;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3114-5208","authenticated-orcid":true,"given":"G.R. 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