Basal Cells Contribute to Pulmonary Fibrosis via SP1-Mediated Senescence-Associated Secretory Phenotype

Idiopathic pulmonary fibrosis is a progressive interstitial lung disease with limited treatment options and poor prognosis. Increasing evidence suggests that airway epithelial remodeling contributes to disease pathogenesis, yet the role of basal cells remains incompletely understood. This study aimed to determine whether basal cells participate in pulmonary fibrosis through a senescence-associated secretory phenotype regulated by the transcription factor SP1.

Lung tissue from patients with idiopathic pulmonary fibrosis who underwent transbronchial cryobiopsy was compared with control samples from patients undergoing lung resection for benign nodules. Histopathological analysis and immunohistochemistry were used to evaluate basal cell distribution and quantify cell-specific markers. Transcriptomic data from the GEO database were analyzed to identify differentially expressed genes and enriched signaling pathways. Findings were validated in a bleomycin-induced pulmonary fibrosis mouse model, and SP1 expression was assessed by protein analysis.

Basal cells were markedly increased in fibrotic airways and extended from bronchioles into fibroblast foci, with their abundance correlating positively with fibrosis severity. Differential gene expression analysis identified enrichment of senescence-associated secretory phenotype-related pathways, including upregulation of metalloproteinases and chemokines. In the mouse model, senescence-associated mediators were significantly elevated, and SP1 expression was increased in fibrotic lungs.

Basal cells may actively contribute to pulmonary fibrosis, and SP1-mediated senescence-associated secretory phenotype may represent a potential novel pathogenic mechanism. Targeting basal cell dysfunction or SP1-related pathways may offer new therapeutic opportunities for idiopathic pulmonary fibrosis.