The cGAS-STING Pathway: Novel Perspectives in Liver Diseases

Abstract

Liver diseases represent a major global health burden accounting for approximately 2 million deaths per year worldwide. The liver functions as a primary immune organ that is largely enriched with various innate immune cells, including macrophages, dendritic cells, neutrophils, NK cells, and NKT cells. Activation of these cells orchestrates the innate immune response and initiates liver inflammation in response to the danger signal from pathogens or injured cells and tissues. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a crucial signaling cascade of the innate immune system activated by cytosol DNA. Recognizing DNA as an immune-stimulatory molecule is an evolutionarily preserved mechanism in initiating rapid innate immune responses against microbial pathogens. The cGAS is a cytosolic DNA sensor eliciting robust immunity via the production of cyclic GMP-AMPs that bind and activate STING. Although the cGAS-STING pathway has been previously considered to have essential roles in innate immunity and host defense, recent advances have extended the role of the cGAS-STING pathway to liver diseases. Emerging evidence indicates that overactivation of cGAS-STING may contribute to the development of liver disorders, implying that the cGAS-STING pathway is a promising therapeutic target. Here, we review and discuss the role of the cGAS-STING DNA-sensing signaling pathway in a variety of liver diseases, including viral hepatitis, nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), primary hepatocellular cancer (HCC), and hepatic ischemia-reperfusion injury (IRI), with highlights on currently available therapeutic options.

Pharmacokinetics and Therapeutic Potential of Teucrium polium, a Medicinal and Endangered Species in Ha'il Region, against Liver Damage Associated Hepatotoxicity and Oxidative Injury in Rats: Computational, Biochemical and Histological Studies

“…CYP and STING receptors have been selected, as they are commonly associated with both liver pathogenesis and are targeted in drug design and development [ 34 , 35 ]. The molecular interactions of T. polium ’s major compounds with these key receptors, which are targeted in liver therapy, were studied.…”

Defective mitophagy in aged macrophages promotes mitochondrial DNA cytosolic leakage to activate STING signaling during liver sterile inflammation

“…STING signaling in macrophages has been implicated in anti‐tumor immunity, cellular senescence, and autoimmune and inflammatory diseases (Motwani et al, 2019 ). Endogenous mtDNA released from injured liver parenchymal cells induces STING activation in macrophages, which in turn augments inflammatory liver damage (Xu et al, 2021 ). During liver IR injury, ROS cause oxidative damage to the mitochondria, leading to the release of cytosolic mtDNA from injured hepatocytes.…”

“…Macrophage‐STING signaling mediated sterile inflammation has been implicated in several liver diseases, such as nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and liver cancer (Xu et al, 2021 ). Damage‐associated molecular patterns (DAMPs) from injured liver parenchymal cells induce the activation of macrophages via various types of pattern recognition receptors (PPRs), leading to an inflammatory response and liver injury.…”

STING Induces Liver Ischemia-Reperfusion Injury by Promoting Calcium-Dependent Caspase 1-GSDMD Processing in Macrophages

“…Innate immunity is the first line of defense against infection, but its excessive activation can result in tissue injury and host lethality [ 27 , 28 ].STING has previously been shown to regulate inflammation and infection in health and disease [ 20 , 29 ]. At present, only a few articles have reported the role of STING in liver IRI [ 30 , 31 ], and the underlying mechanism remains to be determined. In this study, we found that the activation of STING in liver IRI mainly depends on liver macrophages, and that STING promotes the processing of caspase 1-GSDMD in macrophages to aggravate liver IRI.…”