cGAS-STING Targeting Offers Novel Therapeutic Opportunities in Liver Diseases

Abstract

Yumin Wang,1,* Rui Yang,1,* Yuwei Cao,1,* Yulin Li,1 Yonglin Zhu,1 Zhe Zhang,1 Joshua S Fleishman,2 Jichao Chen,1 Mingchao Ding3 1Department of Respiratory and Critical Care Medicine, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, People’s Republic of China; 2Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, 11439, USA; 3Department of Peripheral Vascular Intervention, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingchao Ding, Department of Peripheral Vascular Intervention, Aerospace Center Hospital, Peking University Aerospace School of Clinical Medicine, Beijing, 100049, People’s Republic of China, Email [email protected] Joshua S Fleishman, Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, 11439, USA, Email [email protected]: Cyclic GMP/AMP (cGAMP) synthase (cGAS), coupled with the endoplasmic reticulum (ER)-anchored adaptor protein stimulator of interferon genes (STING), constitute key components of the type 1 interferon signaling network. cGAS detects both pathogen-derived DNA and aberrant cytosolic self-DNA, establishing the cGAS-STING pathway as a central player in autoimmune disorders, sterile inflammation, and senescence-related processes. However, sustained abnormal activation of this signaling axis is implicated in the pathogenesis of chronic inflammatory and autoimmune conditions. Recent studies have uncovered the pivotal role of cGAS-STING signaling in driving inflammation-associated pathologies, particularly hepatic disorders. Advances in understanding the molecular dynamics of this pathway have facilitated the development of targeted small-molecule inhibitors with therapeutic potential for cGAS-STING-driven liver diseases. In this review, we first delineate the core architecture of the cGAS-STING signaling cascade. Building on this framework, we analyze emerging evidence elucidating the mechanistic contributions of cGAS-STING activation to hepatic pathophysiology. Subsequently, we catalog pharmacologically active compounds capable of modulating this pathway in liver disease models. Finally, we critically evaluate current challenges in translating cGAS-STING-targeted therapies and propose strategic approaches to address these limitations. This synthesis underscores innovative therapeutic opportunities arising from precision modulation of the cGAS-STING axis in liver diseases.Keywords: cGAS, STING, antagonist, liver diseases

Keywords

• cGAS
• STING
• Antagonist
• Liver Diseases