Edaravone dexborneol attenuates cerebral Ischemia–Reperfusion injury via cGAS–STING inhibition, STX17-Mediated autophagic flux restoration, and NLRP3 inflammasome suppression

Nov 7, 2025European journal of pharmacology

Edaravone dexborneol may reduce brain damage after stroke by blocking inflammation, restoring cell cleanup, and lowering immune response

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Abstract

Edaravone dexborneol (EDB) treatment reduced infarct volume and neurological deficits in a rat model of ischemic stroke.

EDB treatment significantly lowered cerebral edema and preserved mitochondrial membrane potential.
The treatment also reduced neuronal apoptosis during reperfusion.
Inhibition of the cGAS-STING pathway was observed, which may regulate autophagy and inflammation.
EDB promoted the fusion of autophagosomes with lysosomes and restored autophagic flux.
Activation of the NLRP3 inflammasome and related gene expression was suppressed by EDB.
Rescue experiments indicated that the cGAS-STING axis plays a central role in EDB's protective effects.

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Acute ischemic stroke (AIS) is a leading cause of death and disability worldwide. Although intravenous thrombolysis and mechanical thrombectomy improve vascular recanalization, reperfusion often induces secondary cerebral ischemia-reperfusion injury (CI/RI), which limits therapeutic efficacy. Edaravone dexborneol (EDB) has been validated in large phase II and III clinical trials to be safe and effective in improving 90-day functional outcomes in AIS patients. However, the precise mechanisms by which EDB confers neuroprotection during reperfusion remain unclear. In this study, we employed a rat middle cerebral artery occlusion/reperfusion (MCAO/R) model and oxygen-glucose deprivation/reoxygenation (OGD/R) microglial model to investigate the mechanistic effects of EDB. We found that EDB treatment markedly reduced infarct volume, cerebral edema, and neurological deficits, while preserving mitochondrial membrane potential and alleviating neuronal apoptosis. Mechanistically, EDB inhibited the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which acted as an upstream regulatory hub. This inhibition promoted Syntaxin 17 (STX17)-mediated autophagosome-lysosome fusion and restored autophagic flux, while simultaneously suppressing NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and pyroptosis-related gene expression. Rescue experiments with the STING agonist 2'3'-cyclic GMP-AMP (2'3'-cGAMP) reversed these protective effects, confirming the central role of the cGAS-STING axis. In conclusion, this study identifies a novel mechanism whereby EDB alleviates CI/RI through dual regulation of autophagy and inflammation via inhibition of cGAS-STING signaling. These findings not only provide new mechanistic insights but also support the clinical potential of EDB as an adjunctive therapy for AIS reperfusion injury.

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Edaravone dexborneol attenuates cerebral Ischemia–Reperfusion injury via cGAS–STING inhibition, STX17-Mediated autophagic flux restoration, and NLRP3 inflammasome suppression

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