The role of cGAS-STING signaling in pulmonary fibrosis and its therapeutic potential

Abstract

Pulmonary fibrosis is a progressive and ultimately fatal lung disease, exhibiting the excessive production of extracellular matrix and aberrant activation of fibroblast. While Pirfenidone and Nintedanib are FDA-approved drugs that can slow down the progression of pulmonary fibrosis, they are unable to reverse the disease. Therefore, there is an urgent demand to develop more efficient therapeutic approaches for pulmonary fibrosis. The intracellular DNA sensor called cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) plays a crucial role in detecting DNA and generating cGAMP, a second messenger. Subsequently, cGAMP triggers the activation of stimulator of interferon genes (STING), initiating a signaling cascade that leads to the stimulation of type I interferons and other signaling molecules involved in immune responses. Recent studies have highlighted the involvement of aberrant activation of cGAS-STING contributes to fibrotic lung diseases. This review aims to provide a comprehensive summary of the current knowledge regarding the role of cGAS-STING pathway in pulmonary fibrosis. Moreover, we discuss the potential therapeutic implications of targeting the cGAS-STING pathway, including the utilization of inhibitors of cGAS and STING.

Keywords: cGAS-STING; inhibitors; pulmonary fibrosis; signaling pathway; therapeutic potential.

Figure 1

Schema outlining the history of interferon discovery and important events related to cGAS and STING biology.

Figure 2

Schematic diagram of the cGAS-STING signaling pathway. The cGAS-STING pathway is initiated by the detection of cytosolic DNA, including nucleic acids from pathogens and self-DNA. When cytosolic DNA is recognized, cGAS binds to STING, leading to the translocation of STING from the endoplasmic reticulum (ER) to the Golgi and post-Golgi compartments. This activation of STING triggers the phosphorylation of IRF3 by TBK1, resulting in gene expression of type I interferons. Additionally, STING activates NF-κB through the phosphorylation of the kinase IKK, leading to the activation of genes involved in inflammation and immune responses.

Figure 3

Secretion of immune inflammatory factors, such as TNF-α, IFN-β induced by the cGAS-STING pathway in the progression of pulmonary fibrosis.

Figure 4

Schematic structure of human STING, and mutation sites leading to pulmonary fibrosis.

Figure 5

Natural products, such as PPD, heterophyllin B, juglanin, TRQ, alleviate pulmonary fibrosis by inhibiting STING.

Figure 6

Activation of the cGAS-STING signaling pathway leads to further exacerbation of pulmonary fibrosis through multiple pathways of cellular senescence.

Figure 7

GMWCNT and silica induces pulmonary inflammation and fibrosis via activation of the cGAS-STING signaling pathway.