The dual function of cGAS-STING signaling axis in liver diseases.

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.