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<p>Pulmonary fibrosis represents a progressive interstitial lung disease marked by excessive extracellular matrix deposition and architectural distortion. Vascular endothelial cells critically contribute to fibrogenesis through paracrine secretion of pro-fibrotic mediators, yet their mechanobiological regulation remains elusive. Using integrated single-cell multi-omics profiling of human pulmonary fibrosis specimens and experimental fibrosis models induced by bleomycin or silica, we identify mechanosensitive <i>Piezo1</i> upregulation in Endothelial cells as a hallmark of fibrotic progression. Endothelial-specific <i>Piezo1</i> knockout significantly attenuates Bleomycin-induced fibrotic remodeling in male mice, establishing its pathogenic necessity. Mechanistically, PIEZO1 activation promotes pulmonary fibrosis development via CAPN2-mediated STAT3 phosphorylation, which may regulate the secretion of the pro-fibrotic molecule interleukin-33. These findings suggest that the endothelial PIEZO1-CAPN2-STAT3-IL33 axis is a potential therapeutic target for PF intervention.</p>

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Single-cell multiomics uncovers an endothelial mechanosensitive PIEZO1-IL-33 axis driving pulmonary fibrosis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月20日

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  • Lanlan Zhang,
  • Xuezhen Gui,
  • Ruijie Hou,
  • Liping Jia,
  • Shu Xia,
  • Xin Zhang,
  • Yingyun Fu,
  • Qian-Fang Meng,
  • Qun Luo,
  • Xing Shi,
  • Bingxin Guo,
  • Ruifang Liang,
  • Ludan Yue,
  • Xue Chen,
  • Haizhao Xu,
  • Pengbo Wang,
  • Xia Tong,
  • Lujie Liu,
  • Lingwei Wang,
  • Baicun Li,
  • Zi Chen,
  • Linfu Zhou,
  • Linshu Zhang,
  • Rongchang Chen,
  • Changbin Sun,
  • Wei Xu,
  • Lang Rao,
  • Haibo Zhou,
  • Bi-Sen Ding,
  • Shanze Chen

摘要

Pulmonary fibrosis represents a progressive interstitial lung disease marked by excessive extracellular matrix deposition and architectural distortion. Vascular endothelial cells critically contribute to fibrogenesis through paracrine secretion of pro-fibrotic mediators, yet their mechanobiological regulation remains elusive. Using integrated single-cell multi-omics profiling of human pulmonary fibrosis specimens and experimental fibrosis models induced by bleomycin or silica, we identify mechanosensitive Piezo1 upregulation in Endothelial cells as a hallmark of fibrotic progression. Endothelial-specific Piezo1 knockout significantly attenuates Bleomycin-induced fibrotic remodeling in male mice, establishing its pathogenic necessity. Mechanistically, PIEZO1 activation promotes pulmonary fibrosis development via CAPN2-mediated STAT3 phosphorylation, which may regulate the secretion of the pro-fibrotic molecule interleukin-33. These findings suggest that the endothelial PIEZO1-CAPN2-STAT3-IL33 axis is a potential therapeutic target for PF intervention.