Mechanisms and Therapeutic Targeting of the cGAS-STING Pathway in Central Nervous System Disorders.

OBJECTIVE

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway is a core DNA-sensing axis in innate immunity and has been increasingly implicated in the pathogenesis of multiple Central Nervous System (CNS) disorders. This review summarizes current knowledge of cGAS-STING signaling in CNS disorders and evaluates its therapeutic potential.

METHODS

Relevant studies on cGAS-STING signaling in CNS disorders were collected from PubMed and Web of Science, with emphasis on disease mechanisms, neuroinflammatory regulation, and pathway-targeted therapeutic strategies.

RESULTS

In the CNS, cGAS-STING signaling exhibits marked region-, cell-, and pathology-dependent heterogeneity. Aberrant DNA sensing activates this pathway and amplifies neuroinflammation, cellular stress, and tissue injury in Alzheimer's Disease (AD), Parkinson's Disease (PD), Amyotrophic Lateral Sclerosis (ALS), ataxia-telangiectasia (A-T), and ischemic and hemorrhagic stroke. Pharmacological inhibition of cGAS, cyclic GMP-AMP (cGAMP), or STING, together with emerging delivery strategies, has shown promise in preclinical models.

DISCUSSION: Clinical translation remains limited by incomplete validation of pathway specificity, limited human evidence, restricted brain delivery, and inconsistent efficacy assessment.

CONCLUSION

The cGAS-STING pathway links aberrant DNA sensing to innate immune activation and CNS pathology. Clarifying its disease-, cell-, and stage-specific roles may support future targeted therapeutic strategies for CNS disorders.