In order to explore whether αCGRP (Calca) deficiency aggravates pulmonary fibrosis (PF). Clinical data from patients with PF (n= 52) were retrospectively analyzed. Lung tissue from a bleomycin (BLM)-induced rat model was compared with that ofCalca-knockout (KO) and wild type (WT) using immunohistochemistry, RNA-seq, and UPLC-MS/MS metabolomic analyses. The results showed that decreased αCGRP expression and activation of the type 2 immune response were detected in patients with PF. In BLM-induced andCalca-KO rats, αCGRP deficiency potentiated apoptosis of AECs and induced M2 macrophages. RNA-seq identified enrichment of pathways involved in nuclear translocation and immune system disorders inCalca-KO rats compared to WT. Mass spectrometry of lung tissue fromCalca-KO rats showed abnormal lipid metabolism, including increased levels of LTB4, PDX, 1-HETE. PPAR pathway signaling was significantly induced in both transcriptomic and metabolomic datasets inCalca-KO rats, and immunofluorescence analysis confirmed that the nuclear translocation of PPARγ in BLM-treated andCalca-KO rats was synchronized with STAT6 localization in the cytoplasmic and nuclear fractions. In conclusion, αCGRP is protective against PF, and αCGRP deficiency promotes M2 polarization of macrophages, probably by activating the PPARγ pathway, which leads to activation of the type 2 immune response and accelerates PF development.