cGAS-STING targeting offers a novel therapeutic paradigm in hemorrhagic stroke.

Abstract

As a pivotal module of the innate immune system, the cGAS-STING signaling pathway is responsible for sensing cytosolic DNA and triggering inflammatory reactions, and it exerts a vital function in the pathological progression of hemorrhagic stroke.This review synthesizes current evidence on the involvement of cGAS-STING in both intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), highlighting its activation by damage-associated molecular patterns (DAMPs) such as neutrophil extracellular traps (NETs) and mitochondrial DNA (mtDNA). In ICH, cGAS-STING activation in microglia and astrocytes drives neuroinflammation, promotes pyroptosis via inflammasome assembly, disrupts blood-brain barrier (BBB) integrity, and exacerbates secondary brain injury. In SAH, the pathway is engaged through cytosolic mtDNA release and transcellular cGAMP transfer from neurons to microglia, amplifying neuroinflammation, ferroptosis, NLRP3 inflammasome activation, and autophagic dysfunction. Therapeutic targeting of cGAS-STING with pharmacological inhibitors (e.g., RU.521, H-151), genetic interventions, and cell-based strategies demonstrates significant neuroprotection in preclinical models, attenuating inflammation, preserving BBB function, and improving neurological outcomes. Collectively, the cGAS-STING axis emerges as a pivotal integrative mechanism and promising therapeutic target for mitigating brain injury following hemorrhagic stroke.