The Role of the cGAS-STING Pathway in Central Nervous System Diseases

In recent years, the cGAS-STING signaling pathway has emerged as a highly regarded mechanism for intracellular DNA recognition and innate immune activation. This pathway activates downstream interferon and inflammatory factor expression by recognizing Double-Stranded DNA (dsDNA) in the cytoplasm, thereby participating in the regulation of various physiological and pathological processes, including autophagy, apoptosis, and aging. In Central Nervous System (CNS) diseases, abnormal activation of the cGAS-STING pathway is closely associated with key pathological mechanisms such as neuroinflammation and neuronal injury. However, its specific mechanisms of action and regulatory networks in different diseases still require systematic investigation. This paper provides a systematic review summarizing the molecular activation mechanisms of the cGAS-STING signaling pathway, with a focus on elucidating its role and mechanisms of action in various central nervous system disorders. We further explored the potential and challenges of this pathway as a therapeutic target. This paper provides a comprehensive and categorized analysis of the composition, activation process, and functional roles of the cGAS-STING pathway in CNS diseases, based on the latest research findings. By reviewing preclinical research evidence, this study focuses on investigating the activation triggers of this pathway across various disease models and their impact on disease progression. While summarizing current pharmacological research advances targeting this pathway. Reviews indicate that the cGAS-STING pathway is activated in various CNS disorders, primarily exacerbating secondary neurological damage by inducing glial cells to polarize toward a proinflammatory phenotype and perpetuating neuroinflammation. Preclinical studies indicate that cGAS or STING inhibitors (such as C-176, H-151, RU.521, etc.) effectively reduce neuroinflammation and improve behavioral outcomes, suggesting significant therapeutic potential. However, the translational application of this pathway still faces significant challenges, including poor blood-brain barrier penetration of existing inhibitors, suboptimal pharmacokinetic properties, potential off-target toxicity, and the risk of immunosuppression that may arise from long-term inhibition. Moreover, this pathway may exert dual or even opposing effects across different disease stages and cell types, exhibiting significant context-dependent functionality. The cGAS-STING pathway plays a crucial role in neuroimmunoregulation of CNS diseases and represents a highly promising therapeutic intervention target. Despite the exciting preclinical evidence, its translation into clinical applications remains constrained by numerous challenges, including drug delivery, selectivity, safety, and potential interference with physiological immune function. Future research should focus on elucidating the precise regulatory network of this pathway in specific pathological contexts and developing novel modulators with high blood-brain barrier permeability, high selectivity, and favorable safety profiles. Concurrently, conduct systematic efficacy and safety validation in models more closely resembling human diseases to advance the ultimate realization of targeted therapeutic strategies for this pathway. Activation of the cGAS-STING signalling pathway and its role in central nervous system diseases. (ICH: Intracerebral hemorrhage; TBI: Traumatic brain injury).