Syndecan-1 Promotes Alveolar Type 2 Epithelial Cell Senescence during Lung Fibrosis.

Yao, C.; Espinola, M.; Liu, X.; Wang, Y.; Zuttion, M.; Kuchibhotla, V.; Zhang, X.; Prata, L. L.; Cho, S.; Ortega, Z.; Braghramian, E.; Merene, K.; Jackman, S.; Caudill, A.; Contreras, F.; Liang, J.; Jiang, D.; Noble, P. W.; Hogaboam, C. M.; Stripp, B. R.; Lopez-Martinez, C.; Gharib, S. A.; Seng, A.; Bottini, N.; Parks, W. C.; Chen, P.; Parimon, T.

doi:10.64898/2026.03.16.712248

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bioRxiv · 10.64898/2026.03.16.712248

Syndecan-1 Promotes Alveolar Type 2 Epithelial Cell Senescence during Lung Fibrosis.

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Abstract

Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive, and fatal interstitial lung disease for which effective therapies remain limited. 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-based 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-driven epithelial dysfunction as a potential therapeutic strategy.

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Yao, C., Espinola, M., Liu, X., Wang, Y., Zuttion, M., Kuchibhotla, V., Zhang, X., Prata, L. L., Cho, S., Ortega, Z., Braghramian, E., Merene, K., Jackman, S., Caudill, A., Contreras, F., Liang, J., Jiang, D., Noble, P. W., Hogaboam, C. M., Stripp, B. R., Lopez-Martinez, C., Gharib, S. A., Seng, A., Bottini, N., Parks, W. C., Chen, P., Parimon, T.. 2026-03-18. Syndecan-1 Promotes Alveolar Type 2 Epithelial Cell Senescence during Lung Fibrosis.. https://doi.org/10.64898/2026.03.16.712248

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