The cGAS-STING pathway in traumatic brain injury: mechanisms of neuroinflammation and therapeutic strategies

Traumatic brain injury (TBI) remains a leading cause of mortality and long-term disability worldwide, and no pharmacological therapy interrupts the deleterious secondary injury cascade. Damage-associated molecular patterns (DAMPs), particularly mislocalized nuclear and mitochondrial DNA, drive self-sustained neuroinflammation by activating the cytosolic DNA-sensing cGAS–STING pathway to trigger type-I interferon and NF-κB-dependent transcription. This review summarizes cGAS-STING molecular features, cell-specific activation, temporal kinetics and therapeutic strategies in TBI. Genetic studies from focal and diffuse injury models demonstrate that cGAS-STING ablation lessens lesion volume, mitigates neuroinflammation and preserves cognitive function, with microglia acting as the predominant cellular mediator. Clinical observations show that cell-free mitochondrial DNA, a major cGAS ligand, is markedly elevated in severe TBI patients’ cerebrospinal fluid and serum, correlating with injury severity and prognosis, while aging amplifies pathway activation. Positioned at the intersection of DAMP sensing, glial reactivity, cell-death signaling and chronic neurodegeneration, cGAS-STING represents a highly promising therapeutic target for post-traumatic neuroinflammation.