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<p>Cigarette smoking is the most dominant factor contributing to chronic obstructive pulmonary disease (COPD). Fibroblasts are sensitive to cellular injury induced by cigarette smoke condensate (CSC). This study was devoted to discovering the potential target and exploring its regulatory mechanism in CSC-induced human fibroblasts. Network pharmacological analysis for differential genes in CSC-induced lung fibroblasts MRC5 was performed by a bioinformatics platform. COPD in vitro was induced by CSC in MRC5. The protein expression was analyzed by western blotting. Cellular senescence was tested by senescence-associated β-galactosidase assay and protein detection. Oxidative indexes were examined by corresponding&#xa0;kits. Inflammatory factors were detected using enzyme-linked immunosorbent assay. Markers associated with the TGF-β1/Smad2/3 pathway and fibrosis were also determined via western blotting. FOXO1 and TGF-β1 binding was analyzed by ChIP assay. An animal model was established to explore the effect of FOXO1 in vivo. Gene Ontology (GO) analysis of the differential genes in CSC-induced MRC5 cells indicated gene functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed the top 10 pathways. Forkhead box O 1 (FOXO1) was an upregulated gene in the cellular senescence pathway. Cell function assays suggested that FOXO1 knockdown restrained CSC-induced cellular senescence, oxidative stress, and inflammation in MRC5. FOXO1 downregulation inactivated the TGF-β1/Smad2/3 pathway and suppressed fibrosis markers in CSC-treated MRC5 cells. FOXO1 directly interacted with TGF-β1 promoter and facilitated cell senescence by upregulating TGF-β1. TGF-β1 abolished the suppression of TGF-β1/Smad2/3 pathway and fibrosis caused by FOXO1 knockdown. FOXO1 promoted COPD in mice by regulating the TGF-β1/Smad2/3 pathway. The obtained evidence affirmed that FOXO1 contributed to CSC-induced cellular senescence and fibrosis by promoting TGF-β1 transcription to mediate the TGF-β1/Smad2/3 pathway, indicating an important mechanism in the pathogenesis of COPD.</p>

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FOXO1 contributes to cigarette smoke condensate–induced cellular senescence and fibrosis in lung fibroblasts through activating the TGF-β1/Smad2/3 signaling pathway

  • 期刊论文

  • 发表日期：

    2025年6月11日

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  • Mengning Zheng,
  • Guohang Yuan,
  • Jing Han,
  • Jiayi Li,
  • Youjun Jiang,
  • Zhaoxia Li,
  • Yang Yao

摘要

Cigarette smoking is the most dominant factor contributing to chronic obstructive pulmonary disease (COPD). Fibroblasts are sensitive to cellular injury induced by cigarette smoke condensate (CSC). This study was devoted to discovering the potential target and exploring its regulatory mechanism in CSC-induced human fibroblasts. Network pharmacological analysis for differential genes in CSC-induced lung fibroblasts MRC5 was performed by a bioinformatics platform. COPD in vitro was induced by CSC in MRC5. The protein expression was analyzed by western blotting. Cellular senescence was tested by senescence-associated β-galactosidase assay and protein detection. Oxidative indexes were examined by corresponding kits. Inflammatory factors were detected using enzyme-linked immunosorbent assay. Markers associated with the TGF-β1/Smad2/3 pathway and fibrosis were also determined via western blotting. FOXO1 and TGF-β1 binding was analyzed by ChIP assay. An animal model was established to explore the effect of FOXO1 in vivo. Gene Ontology (GO) analysis of the differential genes in CSC-induced MRC5 cells indicated gene functions and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis showed the top 10 pathways. Forkhead box O 1 (FOXO1) was an upregulated gene in the cellular senescence pathway. Cell function assays suggested that FOXO1 knockdown restrained CSC-induced cellular senescence, oxidative stress, and inflammation in MRC5. FOXO1 downregulation inactivated the TGF-β1/Smad2/3 pathway and suppressed fibrosis markers in CSC-treated MRC5 cells. FOXO1 directly interacted with TGF-β1 promoter and facilitated cell senescence by upregulating TGF-β1. TGF-β1 abolished the suppression of TGF-β1/Smad2/3 pathway and fibrosis caused by FOXO1 knockdown. FOXO1 promoted COPD in mice by regulating the TGF-β1/Smad2/3 pathway. The obtained evidence affirmed that FOXO1 contributed to CSC-induced cellular senescence and fibrosis by promoting TGF-β1 transcription to mediate the TGF-β1/Smad2/3 pathway, indicating an important mechanism in the pathogenesis of COPD.