Semaglutide reverses pulmonary fibrosis in mice by inhibiting cellular senescence via Sirt1/HSF1/HSPs pathway activation

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease with no effective treatments. Current therapies often fall short, highlighting an urgent need for novel approaches. Cellular senescence, a state of irreversible growth arrest, is increasingly recognized as a key driver in IPF pathogenesis, contributing to chronic inflammation and tissue remodeling. Given its established metabolic benefits and anti-inflammatory properties, Semaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is being explored for its potential beyond diabetes and obesity, specifically in conditions involving cellular stress and inflammation.

Researchers established an in vivo mouse model of lung fibrosis using bleomycin to induce disease, treating animals with Semaglutide. To dissect the molecular mechanisms, they used shRNA to silence heat shock factor 1 (HSF1) or administered a Sirt1 inhibitor. In vitro, a mouse lung epithelial cell senescence model was created using hydrogen peroxide (H2O2) and similarly treated with Semaglutide. Key anti-senescence targets were identified via transcriptomics, followed by siRNA silencing of HSF1. PCR arrays and co-immunoprecipitation experiments further explored HSPs regulation and interactions.

Semaglutide significantly improved pulmonary fibrosis, oxidative stress, and cellular senescence in the in vivo mouse model. It also effectively inhibited hydrogen peroxide-induced cellular senescence in the in vitro lung epithelial cell model. The observed beneficial effects of Semaglutide were notably inhibited by silencing HSF1 or by Sirt1 inhibition, indicating their critical roles in its mechanism of action. Further investigation revealed that Semaglutide promoted HSF1 protein deacetylation through Sirt1, which subsequently led to an increased expression of various heat shock proteins (HSPs) downstream of HSF1. This Sirt1-mediated deacetylation of HSF1 enhanced HSF1's binding to HSP gene promoters.

Semaglutide inhibited cellular senescence and exerted anti-pulmonary fibrosis effects through the Sirt1 protein-mediated deacetylation of HSF1, enhancing HSF1 binding to HSP gene promoters and increasing HSP expression.