Study on the Efficacy and Pharmacological Mechanism of Innate Immune STING Pathway Regulators in the Treatment of Ischemic Brain Injury

Background/Objectives: The efficacy of ST909, an innate immune cGAS/STING/IRF3 pathway regulator, against ischemic brain injury was investigated, and its pharmacological mechanism was elucidated. Methods: The efficacy and pharmacological mechanism of ST909 in ischemic brain injury were evaluated using the middle cerebral artery occlusion (MCAO) rat model, with brain tissue staining, MRI, behavioral tests (balance beam, screen), and ELISA detection of brain injury markers (neuron-specific enolase [NSE], homocysteine [Hcy], and S100β). Results: ST909 significantly reduces cerebral ischemic area, restores blood–brain barrier integrity, and improves neuronal function, outperforming clinical drugs (3-n-butylphthalide and edaravone) in preclinical models. ST909 markedly reduces neuroinflammation while upregulating neurotrophic factors (e.g., BDNF, NGF) in brain tissue. Through PI3K/Akt pathway activation in microglia, ST909 induces M1-to-M2 phenotype polarization, rebalances the M1/M2 ratio, and enhances secretion of anti-inflammatory cytokines and neurotrophic factors, thereby reducing chronic inflammation and promoting neurological recovery. These findings elucidate ST909’s potential pharmacological mechanism against ischemic brain injury, involving microglial polarization via STING/IRF3 and PI3K/Akt pathway. Conclusions: ST909 has a significant pharmacological effect on improving the ischemic area of the brain and repairing the function of the brain neuronal tissues. Targeting the STING/IRF3 pathway, ST909 exhibits neurorestorative potential in post-ischemic brain injury recovery.