cGAS-STING Signaling Pathway and Liver Disease: From Basic Research to Clinical Practice

Abstract

The cGAS-STING signaling pathway is an autoimmune inflammatory pathway that can trigger the expression of a series of inflammatory factors represented by type 1 interferon. Recent studies have found that the cGAS-STING signaling pathway played a significant role in liver physiology and was closely related to the progress of liver diseases. For example, activating the cGAS-STING signaling pathway could significantly inhibit hepatitis B virus (HBV) replication in vivo. Moreover, the cGAS-STING signaling pathway was also closely associated with tumor immunity in hepatocellular carcinoma (HCC). This review summarized the role of the cGAS-STING signaling pathway in several common liver diseases, especially the current application of the cGAS-STING signaling pathway in liver disease treatment, and prospected its future research, which provided a new idea for understanding and treating liver diseases.

Keywords: CGAS; STING; cancer; inflammation; liver.

FIGURE 1

The activation of cGAS-STING signaling pathway with endogenous DNA as an example. When cGAS bind to DNA, ATP and GTP act as substrates to activate cGAS to catalyze the formation of cGAMP, which is a second messenger to activate STING. cGAMP also transactivates STING in adjacent cells with the help of gap junction proteins such as Cx32. Activated STING is firstly palmitoylated in the Golgi apparatus and then recruits the TBK1. Conversely, the C-terminal domain of STING is phosphorylated by TBK1, and phosphorylated STING recruits RF3, which is also phosphorylated and dimerizes by TBK1. Finally, dimerized IRF3 enters the nucleus and plays its role in the transcription of IFN-1 and ISGs. Moreover, STING can also bind to IKK and activate its mediated NF-κB.

FIGURE 2

Interaction between cGAS-STING signaling pathway and HBV infection. On the one hand, cGAS-STING signaling either produces IFN by activating downstream TLR3 or further activates NF-κB signaling pathway to inhibit intrahepatic HBV replication. On the other hand, HBsAg, HBeAg, or HBV virions inhibit TLR-induced antiviral activity of hepatocytes by suppressing the activation of IRF-3 and NF-κB.

FIGURE 3

The role of the cGAS-STING signaling pathway in HCC. DNA damage leads to the formation of dsDNA in HCC cells, stimulates and activates the cGAS-STING signaling pathway, and promotes the release of IFN-1, which is critical for DC maturation. Then, DCs migrate to tumor-draining lymph nodes with the help of IFN-1 and cross-activate tumor-specific CD8⁺ T cells, and induce systemic antitumor immunity to control local and distant metastasis of tumor growth.