Semaglutide exerts anti-pulmonary fibrosis effects by inhibiting cellular senescence through activation of the Sirt1/HSF1/HSPs pathway.

Idiopathic pulmonary fibrosis is an interstitial lung disease of unknown etiology with no effective treatment. Semaglutide is a glucagon-like peptide-1 receptor agonist that has been widely used in the treatment of diabetes and obesity. This study investigated the therapeutic effects of semaglutide on pulmonary fibrosis and its molecular mechanisms. An in vivo mouse lung fibrosis model was established using bleomycin and treated with semaglutide, and the key targets of semaglutide were explored using heat shock factor 1 (HSF1) shRNA or Sirt1 inhibitor. In vitro, a mouse lung epithelial cell senescence model was established using hydrogen peroxide and treated with semaglutide. Key targets of semaglutide anti-senescence were screened by transcriptomics and the screened HSF1 genes were silenced using siRNA. Semaglutide-regulated HSPs were screened by transcriptomics and PCR arrays and co-immunoprecipitation experiments were conducted to explore key factors in semaglutide promoting increased expression of heat shock proteins (HSPs). We found that semaglutide significantly improved pulmonary fibrosis, oxidative stress and cellular senescence in vivo and inhibited hydrogen peroxide-induced cellular senescence in vitro. Moreover, the above effects were inhibited by silencing HSF1 or Sirt1 inhibition. In addition, semaglutide promoted HSF1 protein deacetylation by Sirt1, leading to the increased expression of HSPs downstream of HSF1. In conclusion, semaglutide inhibited cellular senescence and exerted anti-pulmonary fibrosis effects through the Sirt1 protein-mediated deacetylation of HSF1, which enhances HSF1 binding to the HSP gene promoters and increased the expression of various HSPs.