Background and Purpose: Traumatic brain injury (TBI) remains a major public health concern worldwide with unmet effective treatment. Stimulator of interferon genes (STING) and its downstream type‐I interferon (IFN) signalling are now appreciated to be involved in TBI pathogenesis. Compelling evidence have shown that STING and type‐I IFNs are key in mediating the detrimental neuroinflammatory response after TBI. Therefore, pharmacological inhibition of STING presents a viable therapeutic opportunity in combating the detrimental neuroinflammatory response after TBI.Experimental Approach: This study investigated the neuroprotective effects of the small‐molecule STING inhibitor n‐(4‐iodophenyl)‐5‐nitrofuran‐2‐carboxamide (C‐176) in the controlled cortical impact mouse model of TBI in 10‐ to 12‐week‐old male mice. Thirty minutes post‐controlled cortical impact surgery, a single 750‐nmol dose of C‐176 or saline (vehicle) was administered intravenously. Analysis was conducted 2 h and 24 h post‐TBI.Key Results: Mice administered C‐176 had significantly smaller cortical lesion area when compared to vehicle‐treated mice 24 h post‐TBI. Quantitative temporal gait analysis conducted using DigiGait™ showed C‐176 administration attenuated TBI‐induced impairments in gait symmetry, stride frequency and forelimb stance width. C‐176‐treated mice displayed a significant reduction in striatal gene expression of pro‐inflammatory cytokines Tnf‐α, Il‐1β and Cxcl10 compared to their vehicle‐treated counterparts 2 h post‐TBI.Conclusion and Implications: This study demonstrates the neuroprotective activity of C‐176 in ameliorating acute neuroinflammation and preventing white matter neurodegeneration post‐TBI. This study highlights the therapeutic potential of small‐molecule inhibitors targeting STING for the treatment of trauma‐induced inflammation and neuroprotective potential.

Stimulator of interferon genes (STING)-mediated type-I interferon signaling is a well characterized instigator of the innate immune response following bacterial or viral infections in the periphery. Emerging evidence has recently linked STING to various neuropathological conditions, however, both protective and deleterious effects of the pathway have been reported. Elevated oxidative stress, such as neuroinflammation, is a feature of a number of neuropathologies, therefore, this study investigated the role of the STING pathway in cell death induced by elevated oxidative stress. Here, we report that the H₂O₂-induced activation of the STING pathway is protective against cell death in wildtype (WT) MEFSV40 cells as compared to STING^−/− MEF SV40 cells. This protective effect of STING can be attributed, in part, to an increase in autophagy flux with an increased LC3II/I ratio identified in H₂O₂-treated WT cells as compared to STING^−/− cells. STING^−/− cells also exhibited impaired autophagic flux as indicated by p62, LC3-II and LAMP2 accumulation following H₂O₂ treatment, suggestive of an impairment at the autophagosome-lysosomal fusion step. This indicates a previously unrecognized role for STING in maintaining efficient autophagy flux and protecting against H₂O₂-induced cell death. This finding supports a multifaceted role for the STING pathway in the underlying cellular mechanisms contributing to the pathogenesis of neurological disorders.