Fibroblast growth factor-inducible 14 accelerates pulmonary fibrosis by inducing fibroblast senescence in mice.

Pulmonary fibrosis (PF) is a chronic and fatal aging-related pulmonary disease. Emerging evidence suggests that fibroblast senescence plays a pivotal role in the initiation and progression of PF. Senescent fibroblasts accumulate in fibrotic lungs, driving excessive extracellular matrix (ECM) deposition, which disrupts tissue architecture and compromises pulmonary function. Notably, senolytic therapy targeting these senescent fibroblasts has shown significant efficacy in ameliorating PF. Therefore, elucidating the mechanisms underlying fibroblast senescence is a promising approach to prevent PF. Herein, our results identify fibroblast growth factor-inducible 14 (Fn14) as a critical mediator in the senescence of fibroblasts. We found that Fn14 was up-regulated in pulmonary fibroblasts from both PF patients and bleomycin (BLM)-treated mice. While knockdown of Fn14 attenuated pulmonary structural disruption and reduced fibroblast senescence in the lung of BLM-treated mice. In vitro, Fn14 activation promoted cellular senescence in pulmonary fibroblasts. Mechanistically, Fn14-induced mitophagy impairment resulted in mitochondrial DNA (mtDNA) leakage, which subsequently activated the cGAS-STING signaling. Moreover, restoring mitophagy or inhibiting cGAS ameliorated fibroblast senescence induced by Fn14 activation. Collectively, these results provide comprehensive insight into the pro-fibrotic role of Fn14 in the development of PF by inducing fibroblast senescence and shed light on the Fn14-targeting therapeutics for PF.