BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and lethal lung disease with elusive pathogenesis. Accumulating evidence implicates cellular senescence as a key mechanism in IPF. Current therapies (pirfenidone/nintedanib) reduce acute exacerbation risk and delay lung function decline in mild-to-moderate IPF, but adverse effects often limit their use. The JAK/STAT pathway is critically involved in the pathogenesis of IPF. While artesunate (Art) alleviates pulmonary fibrosis in rats through anti-inflammatory actions, its effects on fibrosis via STAT3 inhibition-particularly in murine models and human tissues-remain underexplored.
OBJECTIVE: To determine whether and how Art attenuates pulmonary fibrosis by suppressing lung fibroblast senescence.
METHODS: Pulmonary fibrosis was induced in vivo in mice through intratracheal bleomycin administration. In vitro senescence models included TGF-β-stimulated primary mouse lung fibroblasts and cultured human lung tissue explants. Fibrosis was assessed via hematoxylin and eosin, Masson's trichrome, immunohistochemistry (IHC), immunofluorescence (IF), and Western blot. The expression of senescence-associated markers was analyzed by Western blotting and immunofluorescence (IF).
RESULTS: Art significantly attenuated bleomycin-induced pulmonary fibrosis in mice. It downregulated senescence markers (p53, p21), myofibroblast markers (α-SMA), and collagen-deposition proteins (fibronectin, collagen I). Mechanistically, Art inhibited STAT3 phosphorylation, subsequently suppressing p53-mediated fibroblast senescence.
CONCLUSION: Art demonstrates therapeutic potential for IPF by inhibiting fibroblast senescence through STAT3/p53 signaling axis suppression.
