Therapeutic modulation of cGAS-STING pathway in neurodegeneration.

Abstract

Neurodegenerative diseases are characterized by progressive loss of neurons and chronic neuroinflammation. Emerging evidence highlights the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) plays a pivotal role in the innate immune system by detecting cytosolic DNA and initiating type-1 interferons and pro-inflammatory responses. In NDDs, the accumulation of misfolded or mutant proteins compromises mitochondrial function, leading to the release of mitochondrial or nuclear deoxyribose nucleic acid (DNA) into the cytosol. This aberrant DNA sensing activates the cGAS-STING pathway, triggering sustained neuroinflammatory cascades and contributing to neuronal dysfunction and disease progression. Therefore, this review highlights the role of cGAS-STING pathway as a promising therapeutic target, with pharmacological inhibitors demonstrating the potential to attenuate disease pathology in animal models. Future directions should focus on translating cGAS-STING modulators into clinical applications, optimizing their specificity and safety, and integrating biomarker-based strategies to enable patient stratification and monitor therapeutic efficacy. Modulating this pathway offers a novel and exciting avenue for intervention in currently intractable neurodegenerative conditions.