Activation of the cGAS-STING pathway in monocytes exacerbates pulmonary fibrosis induced by paraquat poisoning

Paraquat (PQ), a total contact Herbicide, triggers progressive pulmonary fibrosis and multiorgan failure. This toxicity occurs via DNA damage-induced mitochondrial dysfunction and dysregulated extracellular matrix (ECM) remodeling, highlighting the urgent need for novel therapeutic strategies. This study systematically investigated monocytic Cyclic GMP-AMP Synthase (cGAS)-stimulator of interferon genes (STING) signaling in PQ-associated fibrotic lung pathology, focusing on its mechanistic involvement in innate immune regulation. Analysis of the single-cell dataset derived from lung tissue of PQ-poisoned patient revealed significant activation of the TGF-β signaling pathway in fibroblasts and marked hyperactivation of the cGAS-STING pathway in monocytes. Cell co-culture assays confirmed that PQ treatment activated the cGAS-STING pathway in monocytes co-cultured with fibroblasts. Consequently, transforming growth factor-β1 (TGF-β1) expression was upregulated, which stimulated fibroblast activation. The pharmacological cGAS antagonist G150 demonstrated significant attenuation of PQ-triggered cGAS-STING pathway in monocytes and downregulated TGF-β1 expression, thereby preventing fibroblast activation in co-culture systems. Similarly, the mouse-specific cGAS inhibitor RU.521 effectively reduced Collagen deposition and fibrosis severity while also improving survival rates in PQ-treated mice. Additionally, RU.521 suppressed pulmonary cGAS activity and reduced levels of downstream cGAS-STING pathway proteins. In conclusion, pharmacological targeting of monocyte-driven cGAS-STING pathway emerges as a promising strategy against PQ-associated fibrotic lung disease.

Monocyte; Paraquat; Pulmonary fibrosis; ScRNA-seq; cGAS-STING.