Stimulator of interferon genes signaling promotes epithelial-mesenchymal transition by inducing programmed death-ligand 1 expression in silicosis.

Silicosis is caused by occupational exposure to respirable crystalline silica (CS) particles and is characterized by chronic inflammation and progressive pulmonary fibrosis. To date, the underlying mechanisms of silicosis remain poorly understood and effective treatment options are limited. Stimulator of interferon genes (STING) has been identified by us and others as a critical initiator of inflammatory responses and lung damage during silicosis. In this study, we investigate the role of STING pathway in regulating programmed death-ligand 1 (PD-L1) expression and epithelial-mesenchymal transition (EMT) during silicosis, and further explore the underlying mechanisms and profibrotic significance of this axis. Our findings demonstrate that STING signaling regulates PD-L1 expression and promotes EMT progression in the silicosis mouse model. Mechanistically, CS-activated macrophage STING signaling induces PD-L1 expression and drives the EMT process in alveolar epithelial cells by the TGF-β1/Smad2/3 signaling pathway. Furthermore, we demonstrate that epithelial PD-L1 mediates CS-induced EMT and fibrogenic activity in alveolar epithelia. Collectively, these findings extend our mechanistic understanding of how STING promotes silicotic fibrosis and identify potential therapeutic targets for silicosis.