Advances in cGAS-STING Signaling in Fibrosis Diseases: Therapeutic Target in Pathological Scars

Abstract

Fibrosis is characterised by an excessive response to tissue injury during wound healing, resulting in excessive scarring, which can affect any organ and lead to deformity or death. Fibrogenesis is a highly orchestrated process in which extracellular matrix deposition becomes unstructured, disrupting normal tissue architecture and subsequently impairing proper organ function through complex molecular signals and cellular responses. Inflammation is an important trigger for both regeneration and fibrosis after tissue damage-particularly due to inflammatory cytokines released by various recruited and activated immune cells-which can provoke an excessive inflammatory response in a short time. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has emerged as a key mediator of inflammation in the context of infection, cellular stress, tissue damage, and fibrosis. This reflects its capacity to sense and regulate cellular responses to ubiquitous danger-associated molecular patterns, mainly microbial or host-derived DNA. The cGAS-STING pathway plays a pivotal role in the development and progression of fibrotic diseases by linking cellular stress and DNA damage to chronic inflammation and fibroblast activation, thereby driving pathological tissue remodeling and extracellular matrix accumulation. However, a systematic summary of cGAS-STING in fibrotic diseases is lacking. Therefore, this review focuses on the effects and molecular mechanisms of cGAS-STING signalling in fibrotic diseases. We outline the principal elements of the cGAS-STING signalling cascade and discuss the mechanisms underlying the association of cGAS-STING activity with fibrosis in different organs. Finally, we elucidate the recently developed cGAS and STING antagonists and summarise their potential clinical applications in fibrotic diseases.

Keywords: cGAS-STING; extracellular matrix; fibroblast; fibrosis; inflammation.

Figure 1

Molecular mechanism of the cGAS-STING signaling. Double-stranded DNA (dsDNA)—from microbes, damaged tissues or dead cells, and injured mitochondria—present in the cytoplasm will be sensed by cyclic GMP-AMP synthase (cGAS). Then cGAS will catalyze ATP and GTP into the second messenger 2′,3′-cyclic GMP-AMP (cGAMP), which will further activate the stimulator of interferon genes (STING) that located at the endoplasmic reticulum in a conformational change of oligomerization. The activated STING will move to Golgi. At Golgi, STING will recruit and phosphorylate the TANK-binding kinase 1 (TBK1) and/or inhibitor of kappa B kinase (IKK), thereafter phosphorylating interferon regulatory factor 3 (IRF3) into dimerization and inhibitor of nuclear factor-kappa B (IκB) into degradation, resulting in IRF3 and nuclear factor-kappa B (NF-κB) activation and translocation into the nucleus to induce transcription of type I interferon (IFN-I) and interferon-stimulated genes (ISGs) as well as proinflammatory cytokines, such as IL-1β, IL-6, TNF-α.

Figure 2

cGAS-STING signaling in pulmonary, hepatic, renal, cardiac, and cutaneous inflammation and fibrosis. In pulmonary fibrosis, polystyrene microplastics (PS-MPs), graphitized multi-walled carbon nanotubes (GMWCNTs), silica and bleomycin could activate cGAS-STING signaling and result in pulmonary inflammation and fibrosis. Previous research also illustrated that STING plays a protective role in pulmonary fibrosis associated with prolonged neutrophilic inflammation. In hepatic fibrosis, TAR DNA-binding protein 43 (TDP-43), transforming growth factor-beta (TGF-β), polystyrene microplastics (PS-MPs), hexafluoropropylene oxide trimer acid (HFPO-TA) and X-box binding protein 1 (XBP1) could upregulate cGAS-STING activation and lead to hepatic stellate cells (HSCs) activation, resulting in hepatic fibrosis. Whereas Oroxylin A could antagonize hepatic fibrosis by cGAS-STING/IRF3-induced HSCs senescence via IRF3 and retinoblastoma (RB) interaction. In renal fibrosis, hypoxia, chronic heat, N6-adenosine-methyltransferase 70 kDa subunit (METTL3), mitochondrial transcription factor A (TFAM) deficiency and protein kinase C-delta (PKC-δ) could activate cGAS-STING signaling and result in renal inflammation and fibrosis. In cardiac fibrosis, cardiomyocytes-derived small extracellular vesicles (sEVs) and hypertension could induce myocardial infarction (MI) and cardiac fibrosis by activating cGAS-STING signaling. In cutaneous fibrosis, the autoimmune disorder is the cause of Systemic Sclerosis and leads to cGAS-STING activation, resulting in fibrosis in the skin. However, burn injury, wound infection or surgery-induced pathological scarring, characterized by excessive accumulation of extracellular matrix (ECM), could be driven through cGAS-STING activation or not is unknown.

Figure 3

Application of inhibitors and natural products targeting cGAS and STING in fibrosis diseases.