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Alveolar type 2 (AT2) epithelial cells serve as facultative stem cells essential for alveolar repair; however, AT2 cell senescence disrupts epithelial regeneration and contributes to fibrotic remodeling in IPF. Syndecan-1 is a transmembrane heparan sulfate proteoglycan predominantly expressed by lung epithelial cells, but its role in AT2 dysfunction during fibrosis is poorly defined. Here, we demonstrate that syndecan-1 is robustly upregulated in AT2 cells in IPF and other fibrotic lung diseases, as well as in murine bleomycin-induced lung fibrosis. Syndecan-1 expression was further enhanced with aging and associated with increased fibrotic burden in aged mice. Using integrated human transcriptomic analyses, mouse genetic models, and epithelial cell\u2013based systems, we show that excess syndecan-1 promotes cell-autonomous epithelial senescence and impairs AT2 progenitor function. Elevated syndecan-1 reduced AT2 renewal capacity, disrupted differentiation, and diminished surfactant protein C level, whereas genetic loss of syndecan-1 attenuated senescence and preserved epithelial function following injury. Together, these findings identify syndecan-1 as a critical epithelial regulator of AT2 senescence and maladaptive repair in pulmonary fibrosis and support targeting syndecan-1\u2013driven epithelial dysfunction as a potential therapeutic strategy.<\/jats:p>","DOI":"10.64898\/2026.03.16.712248","type":"posted-content","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T11:10:15Z","timestamp":1773832215000},"source":"Crossref","is-referenced-by-count":0,"title":["Syndecan-1 Promotes Alveolar Type 2 Epithelial Cell Senescence during Lung Fibrosis"],"prefix":"10.64898","author":[{"given":"Changfu","family":"Yao","sequence":"first","affiliation":[{"name":"Women\u2019s Guild Lung Institute, Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milena","family":"Espinola","sequence":"additional","affiliation":[{"name":"Women\u2019s Guild Lung 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