Silica-induced telomere dysfunction promotes pulmonary fibrosis through the activation of the cGAS-STING pathway

This study aims to elucidate whether silica (SiO₂) induces alveolar epithelial cell senescence through telomere shortening, and to explore the involvement of TERF1 and its subsequent activation of the cGAS-STING pathway in the development of pulmonary fibrosis.

Silicosis was induced in male C57BL/6 mice through intratracheal instillation of silica. Lung tissues collected on days 7, 14, and 28 were assessed by H&E staining, qPCR (telomere length and gene expression), and senescence markers (SA-β-Gal staining, p16/p21 immunohistochemistry). In vitro, BEAS-2B cells (including TERF1-modified) were exposed to SiO₂ (short- and long-term), and the expression level of CST complex, telomere stability genes, shelterin complex, and components of cGAS-STING pathway were analyzed by qPCR or Western blot.

An abnormal increase in cellular senescence was observed in the lung tissues of mice with silica-induced silicosis, accompanied by telomere shortening and downregulation of CST complex, telomere-stabilizing genes, and shelterin complex. In BEAS-2B cells, SiO₂ suppressed proliferation and promoted senescence in a dose- and time-dependent manner. Deficiency in TERF1 exacerbated telomere damage, led to the accumulation of cytoplasmic free DNA, and increased cellular senescence, whereas overexpression of TERF1 maintained telomeric homeostasis and attenuated cellular senescence. SiO₂ also activated the cGAS-STING pathway, suggesting its involvement in fibrotic signaling.

Our study found that TERF1 deficiency is key in SiO₂-induced fibrosis, linking telomere instability to cGAS-STING activation through cytosolic DNA. Increasing TERF1 expression restored telomere balance and blocked fibrosis, offering a new therapeutic target.