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<p>To investigate whether αCGRP (<i>Calca</i>) deficiency exacerbates pulmonary fibrosis (PF) by promoting alveolar type 2 (AT2) cell senescence, we retrospectively analyzed clinical data and lung biopsy samples from PF patients (<i>n</i> = 15). In vivo, lung tissues from <i>Calca</i>-knockout (KO) rats and D-galactose (D-gal)-induced senescence models were analyzed using immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and label-free proteomics. PF patient samples showed low αCGRP expression, AT2 subtype differentiation, and high <i>Calca</i> promoter methylation. In <i>Calca</i><sup>-/-</sup> rats, AT2 differentiation and oxidative lipid metabolism were enhanced, with increased senescence gene signatures. scRNA-seq revealed upregulation of linoleic, α-linolenic, and arachidonic acid metabolism, alongside suppression of oxidative stress responses in AT2 of the <i>Calca</i><sup>-/-</sup> group. D-gal treatment induced alveolitis, fibrotic changes and AT2 subtype differentiation, and the most severe alveolar inflammation was found in <i>Calca</i><sup>-/-</sup>+D-gal rats. Proteomics revealed distinct metabolic pathway alterations between WT + D-gal and <i>Calca</i><sup>-/-</sup>+D-gal, and <i>Calca</i><sup>-/-</sup> and WT + D-gal rats. Differences in metabolic and PPAR pathways were observed between <i>Calca</i><sup>-/-</sup> and <i>Calca</i><sup>-/-</sup>+D-gal rats. Additionally, both D-gal treatment and <i>Calca</i><sup>-/-</sup> affect oxidative phosphorylation. Overall, αCGRP deficiency disrupts AT2 lipid metabolism, and accelerates AT2 inflammatory senescence, ultimately promoting pulmonary fibrosis.</p>

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αCGRP deficiency aggravates pulmonary fibrosis by promoting senescence in alveolar type 2 cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月29日

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  • Xiaoting Lv,
  • Qingquan Chen,
  • Ziying Zhou,
  • Weijing Wu,
  • Xingliang Yu,
  • Yiming Zeng

摘要

To investigate whether αCGRP (Calca) deficiency exacerbates pulmonary fibrosis (PF) by promoting alveolar type 2 (AT2) cell senescence, we retrospectively analyzed clinical data and lung biopsy samples from PF patients (n = 15). In vivo, lung tissues from Calca-knockout (KO) rats and D-galactose (D-gal)-induced senescence models were analyzed using immunohistochemistry, single-cell RNA sequencing (scRNA-seq), and label-free proteomics. PF patient samples showed low αCGRP expression, AT2 subtype differentiation, and high Calca promoter methylation. In Calca-/- rats, AT2 differentiation and oxidative lipid metabolism were enhanced, with increased senescence gene signatures. scRNA-seq revealed upregulation of linoleic, α-linolenic, and arachidonic acid metabolism, alongside suppression of oxidative stress responses in AT2 of the Calca-/- group. D-gal treatment induced alveolitis, fibrotic changes and AT2 subtype differentiation, and the most severe alveolar inflammation was found in Calca-/-+D-gal rats. Proteomics revealed distinct metabolic pathway alterations between WT + D-gal and Calca-/-+D-gal, and Calca-/- and WT + D-gal rats. Differences in metabolic and PPAR pathways were observed between Calca-/- and Calca-/-+D-gal rats. Additionally, both D-gal treatment and Calca-/- affect oxidative phosphorylation. Overall, αCGRP deficiency disrupts AT2 lipid metabolism, and accelerates AT2 inflammatory senescence, ultimately promoting pulmonary fibrosis.