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

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.