cGAS-STING Targeting Offers Novel Therapeutic Opportunities in Liver Diseases
Yumin Wang, Rui Yang, Yuwei Cao, Yulin Li, Yonglin Zhu, Zhe Zhang, Joshua S. Fleishman, Jichao Chen, Mingchao Ding
Abstract
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.