Inhibition of the Microglial cGAS-STING Pathway Improves Neurological Deficits and Long-Term Hydrocephalus Symptoms in Mice with Intraventricular Hemorrhage.

Post-hemorrhagic hydrocephalus (PHH) represents a prevalent clinical form of hydrocephalus, where surgical interventions frequently fail or result in severe complications. While current research underscores the role of innate immunity and neuroinflammation in PHH pathogenesis, the precise mechanisms remain elusive. The cyclic guanylate adenylates synthase-stimulator of interferon genes (cGAS-STING) pathway, a pivotal component of innate immunity, has been implicated in various neuroinflammatory disorders. However, its mechanism of action in PHH has not yet been explored. Here, we propose that sustained activation of the cGAS-STING pathway in microglia following intraventricular hemorrhage (IVH) drives persistent neuroinflammation. Our results showed that dsDNA released from pyroptotic neurons and impaired mitochondrial autophagy in microglia can serve as substrates for cGAS detection, forming a cascade of interconnected pathways. Pharmacological inhibition or conditional knockout of cGAS attenuated global neuroinflammation, suppressed microglial activation, and reduced both pyroptosis-dependent (IL-1β and IL-18) and nonpyroptosis-dependent (TNF-α, IFN-β, and IL-6) cytokine release. Additionally, these interventions mitigated neuronal damage, apoptosis, and hydrocephalus-related neurological deficits after IVH Our results demonstrate that cGAS-STING pathway activation, mediated by neuronal pyroptosis and microglial mitophagy dysfunction, perpetuates post-IVH neuroinflammation. Our findings suggest that targeting cGAS may serve as a promising therapeutic approach for PHH.