Abstract
Innate immune signaling preserves brain integrity during infection and sterile injury but can also drive neurodegeneration and cognitive decline. Over the past 2 decades, work has shown that cytosolic DNA sensing via the cGAS-STING pathway can precondition the brain against ischemic injury while impairing post-stroke recovery. Our interest in this pathway arose from the discovery that tilorone, an antiviral immunomodulator, activated a hypoxia-inducible factor (HIF) reporter. Although pre-stroke tilorone treatment was strongly neuroprotective, mechanistic studies revealed that type I interferon (IFN-I) signaling-rather than canonical HIF activation-mediated this effect. However, STING activation can also impair learning and memory. We therefore review the Janus-like duality of cGAS-STING signaling: transient activation enhances ischemic tolerance, whereas sustained activation suppresses neuronal plasticity. In contrast to HIF-driven metabolic reprogramming and growth factor induction, we propose that cGAS-STING/IFN-I signaling enforces a metabolic austerity program that suppresses energy-intensive processes such as synaptic plasticity. This response is adaptive during ischemia but maladaptive when prolonged, locking neural circuits into a low-plasticity state that undermines cognitive resilience. Evidence across models of stroke, neurodegeneration, aging, demyelination, and traumatic injury highlights both the protective and pathological consequences of this pathway and underscores the need to balance innate immune defense with long-term brain health.