The cGAS-STING pathway at the crossroads of neuroimmunology: bridging innate immunity to aging and neurodegeneration

Mounting evidence indicates that aging and neurodegenerative diseases extensively interact with brain immune processes. Cyclic GMP-AMP synthase (cGAS) recognizes aberrant DNA to produce 2‘3’-cGAMP, which activates STING and subsequently induces the type-I interferon response and transcription of inflammatory factors, leading to neuroinflammation that accelerates various acute and chronic neurological disorders. In this review, we summarized the features of cGAS and STING, and depicted the mechanisms concerning exogenous DNA, mitochondrial DNA, nuclear DNA, and protein phase separation in activating the cGAS-STING pathway. Moreover, the multifunctional roles of the cGAS-STING pathway in aging and neurological disorders were highlighted, and the known cGAS or STING inhibitors for the therapy of neurological disorders were discussed. This review summarizes the intricate interplay between the cGAS-STING pathway and neurodegenerative diseases, underscoring its pivotal role in neurodegenerative processes and brain health.