Dihydroartemisinin alleviates pulmonary fibrosis by modulating the calcium signaling pathway in fibroblasts.

backgroundIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible interstitial lung disease with limited effective treatment options. Dihydroartemisinin (DHA), a water-soluble derivative of artemisinin primarily known for its antimalarial properties, has shown potential antifibrotic effects, although its mechanisms remain unclear. PURPOSE: To investigate the therapeutic effects and underlying molecular mechanisms of DHA in IPF.

methodsNetwork pharmacology and single-cell transcriptomic analyses were used to identify DHA-related target molecules. Molecular docking was performed to assess the binding affinity between DHA and candidate proteins. A bleomycin-induced mouse model of pulmonary fibrosis and a TGF-β-stimulated primary lung fibroblast model were used for in vivo and in vitro validation, respectively.

resultsDHA inhibited fibroblast proliferation and activation by downregulating the calcium signaling pathway. Protein–protein interaction analysis identified CALM1, CAMK,PPP3CA, and NFAT1 as central targets. DHA demonstrated strong binding affinity to these targets in docking analyses. Histopathological staining revealed significant attenuation of bleomycin-induced pulmonary fibrosis, with reduced expression of COL1A1, α-SMA, and Fibronectin. In vitro experiments demonstrated that DHA significantly inhibited the proliferation and migration of primary fibroblasts while concurrently downregulating COL1A1, α-SMA, and Fibronectin expression. Notably, the CAMK inhibitor exhibited effects comparable to those of DHA, suggesting a potential shared mechanistic pathway in modulating fibroblast activity.

conclusionDHA alleviates pulmonary fibrosis by inhibiting the calcium signaling pathway, thereby suppressing fibroblast proliferation and activation.