Activation of the cGAS/STING Pathway Contributes to Neuroinflammation in Diabetes‐Associated Cognitive Decline

ABSTRACT Background and Aim Diabetes‐associated cognitive decline (DACD) is a prevalent central nervous system disorder that lacks effective therapies and remains poorly understood in terms of its underlying mechanisms. The activation of cGAS, a crucial cytosolic nucleic acid sensor for double‐stranded DNA, initiates the STING signaling pathway, which in turn triggers inflammatory responses. Hence, the present study focus on the role of cGAS‐mediated neuroinflammation in the pathogenesis of DACD. Methods We used a diabetic rat model induced by STZ and HFD to investigate the role of cGAS in mediating neuroinflammation during DACD. The NOR test, the MWM test, and changes in hippocampal pathology were used to evaluate the effects of T2DM on cognitive function. The involvement of the cGAS/STING pathway and neuroinflammation was examined to investigate the pathogenesis of DACD. Results We observed activation of cGAS/STING signaling in the hippocampus of DACD rats, as demonstrated by elevated levels of cGAS, cGAMP, STING, phosphorylated IRF3, and phosphorylated p65, as wells as a significant increase in the levels of downstream inflammatory factors including IFN‐β, TNF‐α, and IL‐6. Hippocampal cGAS knockdown significantly suppressed the expression of cGAMP, STING, phosphorylated IRF3, and phosphorylated p65, subsequently ameliorated the inflammatory response in the hippocampus of DACD rats. Furthermore, hippocampal cGAS knockdown alleviated cognitive decline in DACD rats. Conclusion According to our findings, cGAS/STING pathway activation drives neuroinflammation, which ultimately results in the progression of DACD. Moreover, our findings raise possibility that therapeutic targeting of cGAS/STING pathway activity might effectively interfere with the progression of DACD.