Background: Idiopathic pulmonary fibrosis (IPF) is an aging-associated lung disease of unknown etiology with limited effective treatment, characterized by accumulation of senescence cells. cGAS-STING pathway provides a critical paracrine signal inducing the production of senescence-associated secretory phenotype (SASP), implicated in inflammation, accumulation of extracellular matrix and paracrine senescence. We proposed a treatment with STING inhibitor targeting the cGAS-STING pathway in human precision-cut lung slices (hPCLS).

Aim: To investigate the senomorphic effect of STING inhibitor using ex vivo models of pulmonary fibrosis in hPCLS.

Methods: We used two ex vivo models in hPCLS as follows: 1) hPCLS generated from human donor lung tissue treated with bleomycin. 2) hPCLS generated from IPF patients explanted lung tissue. At day 3 were cultured in presence and absence of STING inhibitor for 4 days. Tissue was collected at day 7. Senescence markers were compared by ?-galactosidase staining (SA-?gal), western blot (WB), immunofluorescence, and RT-qPCR analysis. Also, we evaluated cGAS-STING pathway by WB.

Results: Our data showed an increase in SA-?gal-positive cells, as well as mRNA and protein expression of senescence markers such as p21. Treatment with STING inhibitor showed a decrease of these markers. cGAS-STING pathway was significantly activated in both models, while downstream targets of this pathway were inhibited by STING inhibitor. Thus attenuating the secretion of SASP, such as IL-6.

Conclusion: STING inhibitor ameliorates senescence by inhibiting cGAS-STING pathway. Our data suggest STING inhibitors as senomorphics are a new alternative for the treatment of IPF.