Mechanistic insights and therapeutic potential of targeting the cGAS-STING pathway in neurodegenerative diseases.

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA-sensing module that links DNA damage and mitochondrial dysfunction to innate immune activation. Here, we focus on canonical cGAS-STING signaling in the central nervous system (CNS) and discuss non-canonical branches only when directly relevant to neurodegeneration. We summarize structural and activation-termination mechanisms and synthesize cell-type-biased outputs across microglia, astrocytes, neurons, and oligodendroglial lineage cells. We then integrate Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease by mapping shared DNA-stress triggers to multicellular amplification loops and by grading causal evidence from genetic perturbation, pharmacological pathway interference, and correlative human datasets. Finally, we classify inhibitor modalities and emerging enabling technologies while emphasizing translational constraints, including blood-brain barrier (BBB) delivery, long-term safety, human STING-allele diversity, and pharmacodynamic biomarkers. Collectively, we propose an evidence-calibrated framework for judging when cGAS-STING is most plausibly positioned as a causal node, a permissive amplifier, or a secondary correlate in neurodegenerative disease, and where therapeutic translation should proceed cautiously.