Effects of geniposide on cerebral ischemia/reperfusion-induced neuron damage by inhibiting autophagy via cGAS-STING.

AIM OF THE STUDY: This study aimed to investigate the protective effects of Geniposide (GEN) against cerebral ischemia-reperfusion injury by targeting the cGAS-STING pathway and modulating autophagy in neuronal cells.

MATERIALS AND METHODS: In vivo middle cerebral artery occlusion/reperfusion (MCAO/R) model and an in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model to mimic the pathology of cerebral ischemic stroke in humans. Behavioral tests, tissue staining to assess neurological deficits and tissue damage in mice. RNA-Seq analysis, molecular docking, immunofluorescence, western blotting, and transmission electron microscopy to verify the underlying autophagic molecular mechanisms.

RESULTS: GEN significantly reduced cerebral infarction volume and neuronal apoptosis in MCAO/R mice. In OGD/R models, GEN improved cell viability and reduced apoptosis rates. Mechanistically, GEN inhibited cGAS-STING pathway activation, suppressing excessive autophagy observed during ischemia-reperfusion injury. RNA-Seq analysis and molecular docking supported these findings, indicating the involvement of autophagy and the cGAS-STING pathway in GEN-mediated neuroprotection.

CONCLUSION: GEN demonstrates potent neuroprotective effects against cerebral ischemia-reperfusion injury by mitigating neuronal apoptosis and improving neurological functions. These effects are attributed to their ability to modulate autophagy by inhibiting the cGAS-STING pathway. These findings highlight GEN as a promising therapeutic candidate for ischemic stroke treatment.