The Dual Function of CGAS-STING Signaling Axis in Liver Diseases

Overview

Journal Acta Pharmacol Sin

Specialty Pharmacology

Date 2024 Jan 17

PMID 38233527

Authors

Xiao-Jiao-Yang Li

Jiao-Rong Qu

Yin-Hao Zhang

Run-Ping Liu

Affiliations

Soon will be listed here.

Abstract

Numerous liver diseases, such as nonalcoholic fatty liver disease, hepatitis, hepatocellular carcinoma, and hepatic ischemia-reperfusion injury, have been increasingly prevalent, posing significant threats to global health. In recent decades, there has been increasing evidence linking the dysregulation of cyclic-GMP-AMP synthase (cGAS)-stimulator of interferon gene (STING)-related immune signaling to liver disorders. Both hyperactivation and deletion of STING can disrupt the immune microenvironment dysfunction, exacerbating liver disorders. Consequently, there has been a surge in research investigating medical agents or mediators targeting cGAS-STING signaling. Interestingly, therapeutic manipulation of the cGAS-STING pathway has yielded inconsistent and even contradictory effects on different liver diseases due to the distinct physiological characteristics of intrahepatic cells that express and respond to STING. In this review, we comprehensively summarize recent advancements in understanding the dual roles of the STING pathway, highlighting that the benefits of targeting STING signaling depend on the specific types of target cells and stages of liver injury. Additionally, we offer a novel perspective on the suitability of STING agonists and antagonists for clinical assessment. In conclusion, STING signaling remains a highly promising therapeutic target, and the development of STING pathway modulators holds great potential for the treatment of liver diseases.

Citing Articles

Flavonoids and Other Polyphenols: Bioactive Molecules from Traditional Medicine Recipes/Medicinal Plants and Their Potential for Phytopharmaceutical and Medical Application.

Intharuksa A, Kuljarusnont S, Sasaki Y, Tungmunnithum D Molecules. 2024; 29(23).

PMID: 39683916 PMC: 11643739. DOI: 10.3390/molecules29235760.

References

Li X, Sun R, Liu R . Natural products in licorice for the therapy of liver diseases: Progress and future opportunities. Pharmacol Res. 2019; 144:210-226. DOI: 10.1016/j.phrs.2019.04.025. View

Bram Y, Nguyen D, Gupta V, Park J, Richardson C, Chandar V . Cell and Tissue Therapy for the Treatment of Chronic Liver Disease. Annu Rev Biomed Eng. 2021; 23:517-546. PMC: 8864721. DOI: 10.1146/annurev-bioeng-112619-044026. View

Li X, Ge J, Li Y, Cai Y, Zheng Q, Huang N . Integrative lipidomic and transcriptomic study unravels the therapeutic effects of saikosaponins A and D on non-alcoholic fatty liver disease. Acta Pharm Sin B. 2021; 11(11):3527-3541. PMC: 8642447. DOI: 10.1016/j.apsb.2021.03.018. View

Choudhary N, Duseja A . Genetic and epigenetic disease modifiers: non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Transl Gastroenterol Hepatol. 2021; 6:2. PMC: 7724177. DOI: 10.21037/tgh.2019.09.06. View

Voss J, Dhurandhar N . Viral Infections and Obesity. Curr Obes Rep. 2017; 6(1):28-37. DOI: 10.1007/s13679-017-0251-1. View

Chen H, Lu D, Yang X, Hu Z, He C, Li H . One Shoot, Two Birds: Alleviating Inflammation Caused by Ischemia/Reperfusion Injury to Reduce the Recurrence of Hepatocellular Carcinoma. Front Immunol. 2022; 13:879552. PMC: 9130551. DOI: 10.3389/fimmu.2022.879552. View

Mukai K, Konno H, Akiba T, Uemura T, Waguri S, Kobayashi T . Activation of STING requires palmitoylation at the Golgi. Nat Commun. 2016; 7:11932. PMC: 4919521. DOI: 10.1038/ncomms11932. View

Yum S, Li M, Fang Y, Chen Z . TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections. Proc Natl Acad Sci U S A. 2021; 118(14). PMC: 8040795. DOI: 10.1073/pnas.2100225118. View

Luo X, Li H, Ma L, Zhou J, Guo X, Woo S . Expression of STING Is Increased in Liver Tissues From Patients With NAFLD and Promotes Macrophage-Mediated Hepatic Inflammation and Fibrosis in Mice. Gastroenterology. 2018; 155(6):1971-1984.e4. PMC: 6279491. DOI: 10.1053/j.gastro.2018.09.010. View

10.

Ishikawa H, Barber G . STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008; 455(7213):674-8. PMC: 2804933. DOI: 10.1038/nature07317. View

11.

Decout A, Katz J, Venkatraman S, Ablasser A . The cGAS-STING pathway as a therapeutic target in inflammatory diseases. Nat Rev Immunol. 2021; 21(9):548-569. PMC: 8029610. DOI: 10.1038/s41577-021-00524-z. View

12.

Zhang X, Bai X, Chen Z . Structures and Mechanisms in the cGAS-STING Innate Immunity Pathway. Immunity. 2020; 53(1):43-53. DOI: 10.1016/j.immuni.2020.05.013. View

13.

Woodward J, Iavarone A, Portnoy D . c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response. Science. 2010; 328(5986):1703-5. PMC: 3156580. DOI: 10.1126/science.1189801. View

14.

Burdette D, Monroe K, Sotelo-Troha K, Iwig J, Eckert B, Hyodo M . STING is a direct innate immune sensor of cyclic di-GMP. Nature. 2011; 478(7370):515-8. PMC: 3203314. DOI: 10.1038/nature10429. View

15.

Sun L, Wu J, Du F, Chen X, Chen Z . Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2012; 339(6121):786-91. PMC: 3863629. DOI: 10.1126/science.1232458. View

16.

Jeltema D, Abbott K, Yan N . STING trafficking as a new dimension of immune signaling. J Exp Med. 2023; 220(3). PMC: 9930166. DOI: 10.1084/jem.20220990. View

17.

Zhang C, Shang G, Gui X, Zhang X, Bai X, Chen Z . Structural basis of STING binding with and phosphorylation by TBK1. Nature. 2019; 567(7748):394-398. PMC: 6862768. DOI: 10.1038/s41586-019-1000-2. View

18.

Liu S, Cai X, Wu J, Cong Q, Chen X, Li T . Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science. 2015; 347(6227):aaa2630. DOI: 10.1126/science.aaa2630. View

19.

Di Domizio J, Gulen M, Saidoune F, Thacker V, Yatim A, Sharma K . The cGAS-STING pathway drives type I IFN immunopathology in COVID-19. Nature. 2022; 603(7899):145-151. PMC: 8891013. DOI: 10.1038/s41586-022-04421-w. View

20.

Oduro P, Zheng X, Wei J, Yang Y, Wang Y, Zhang H . The cGAS-STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy. Acta Pharm Sin B. 2022; 12(1):50-75. PMC: 8799861. DOI: 10.1016/j.apsb.2021.05.011. View