The cGAS-STING Pathway: A Double-Edged Regulator of Neuroinflammation and Myelin Regeneration

The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a central cytosolic DNA sensor that mediates innate immunity by inducing type I interferons (IFN-I) and proinflammatory cytokines. Although its role in antiviral defense and tumor immunity has been well established, emerging evidence suggests that it is also closely involved in demyelinating diseases of both the central and peripheral nervous systems (PNS). Such diseases, exemplified by multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), are characterized by immune-mediated inflammation, oxidative stress, mitochondrial dysfunction, and impaired myelin regeneration. This review systematically examines the diverse roles of the cGAS-STING pathway in demyelination. We summarize how moderate activation of this pathway promotes protective inflammation and autophagy, facilitating debris clearance and supporting remyelination during the early stages of disease. In contrast, excessive or sustained activation exacerbates neuroinflammation, hinders remyelination, and promotes progressive axonal injury. The involvement of cGAS-STING in T cell polarization, reactive oxygen species (ROS)-mediated injury, and antiviral responses further underscores its dual role in both disease initiation and progression. Understanding the context-dependent effects of cGAS-STING signaling in demyelinating diseases offers valuable insights for developing targeted therapeutic strategies. However, this review also emphasizes that most current evidence is derived from cellular and animal models. Given that the effects of cGAS-STING signaling are highly context dependent and may vary among different demyelinating diseases, disease stages, and cell types, further clinically relevant studies are required to validate its therapeutic potential.