cGAS-STING Targeting Offers Novel Therapeutic Opportunities in Liver Diseases

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.