Idiopathic pulmonary fibrosis is a progressive and fatal lung disease characterized by irreversible tissue scarring, structural distortion, and declining respiratory function. Although currently approved antifibrotic therapies can slow disease progression, they do not stop or reverse fibrosis, highlighting the need to better understand upstream disease mechanisms. Increasing evidence identifies cellular senescence as a central biological process linking aging, epithelial cell vulnerability, mitochondrial dysfunction, and abnormal tissue repair in pulmonary fibrosis. Senescent epithelial and mesenchymal cells remain metabolically active and release a broad array of secreted factors that promote fibroblast activation, persistence of contractile cells, and excessive matrix deposition. Recent advances using single-cell and three-dimensional culture approaches further reveal the accumulation of transitional epithelial cell states that fail to complete normal differentiation and instead perpetuate fibrotic remodeling. These findings suggest that senescence represents not merely a consequence of tissue injury, but a self-sustaining driver of disease progression. This review integrates current mechanistic insights into how cellular senescence coordinates epithelial injury, immune dysregulation, and biomechanical feedback to drive lung fibrosis. We also discuss emerging therapeutic strategies that target senescent cells or their downstream signaling pathways, highlighting their potential to complement existing antifibrotic treatments and enable more effective disease modification.
Suwanprakorn et al. (Tue,) studied this question.