cGAS-STING signaling in Alzheimer's disease: Microglial mechanisms and therapeutic opportunities.

Alzheimer's disease (AD) is increasingly recognized as a neuroinflammatory disorder driven by microglial dysfunction. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a critical role in neuroinflammation and has been strongly implicated in the pathology of AD. Chronic activation of cGAS-STING contributes to neurodegeneration by driving persistent type I interferon release and excessive pro-inflammatory cytokine production. However, the pathway exhibits context-dependent effects. Transient activation promotes antiviral defense, autophagy, and cellular quality control in the central nervous system. Sustained engagement exacerbates neuroinflammation and synaptic loss. Preclinical studies demonstrate that pharmacological inhibitors (such as NR, TSG, H-151, TDI-6750, TDI-8246) mitigate amyloid beta and tau pathology, attenuate microglial reactivity, and enhance cognitive outcomes. Yet, its essential physiological roles, including antimicrobial immunity and autophagy regulation, pose challenges for therapeutic targeting. This potentially disrupts neuroimmune homeostasis. In this review, we highlight the role of cGAS-STING in AD and explore its potential as a therapeutic target using small-molecule drug candidates. Despite these promising findings, challenges remain, including optimizing blood-brain barrier (BBB) penetration, ensuring immune specificity, and addressing long-term safety concerns. Due to these challenges, no cGAS-STING inhibitors have entered clinical trials for AD. However, the future of AD treatment may involve modulation of neuroinflammatory pathways, with cGAS-STING inhibitors playing a central role in reshaping neuroimmune homeostasis.