Targeting the Calcium–mtDNA–cGAS-STING Signaling Nexus: A Novel Redox Mechanism for Nimodipine’s Neuroprotection in Traumatic Brain Injury

Objective: Traumatic brain injury (TBI) induces severe secondary injury where molecular mechanisms remain unclear. This study investigates the involvement of the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) signaling pathway in this process and evaluates the neuroprotective effect of the L-type calcium channel blocker nimodipine, focusing on calcium homeostasis, mitochondrial function, and inflammatory signaling. Methods: Using primary neuronal and mouse TBI models, we assessed outcomes via fluorescent calcium imaging, JC-1 staining, Western blot, quantitative PCR (qPCR)/reverse transcription–quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and behavioral tests. Nimodipine was applied to inhibit L-type channels, specifically testing its role in reducing mitochondrial DNA (mtDNA) release, blocking cGAS-STING activation, and suppressing neuroinflammation. Results: TBI markedly activated the cGAS-STING pathway, increasing pro-inflammatory factors and apoptosis. In the cellular oxygen–glucose deprivation model, calcium overload was directly observed by Fluo-4 AM staining and was associated with subsequent mitochondrial permeability transition pore opening and mtDNA release, identifying this process as a key upstream event for cGAS-STING activation. Nimodipine inhibited intracellular calcium overload, reduced mitochondrial injury and mtDNA release, and consequently suppressed cGAS-STING pathway activation. Both in vivo and in vitro experiments showed dose-dependent decreases in pro-inflammatory factors, along with improved neurological function and attenuated brain tissue pathology. Conclusion: Nimodipine attenuates secondary neuroinflammation and neuronal apoptosis after TBI by inhibiting calcium influx, decreasing mtDNA release, and suppressing cGAS-STING signaling. These results suggest that the Ca 2+ -mtDNA-cGAS-STING axis contributes to TBI pathology and that nimodipine may serve as a potential multitarget therapy. Antioxid. Redox Signal. 00, 000–000.