Raffinose targets the NQO1/NF-κB axis to attenuate DON-driven microglial activation and neuroinflammation via...

Deoxynivalenol (DON), a prevalent mycotoxin in grain crops, can cross the blood-brain barrier (BBB) and cause neuroinflammation and neurobehavioral deficits in humans and animals. To date, the precise molecular mechanisms remain incompletely understood. Herein, we showed that DON triggers neurotoxicity by reprogramming microglial glycolysis via activation of the NQO1/NF-κB pathway. Raffinose (Raf), a natural trisaccharide, effectively attenuated DON-induced neuroinflammation in vivo and in vitro. Mechanistically, Raf upregulated NQO1 transcription by selectively binding to Nrf2 at Val-514 and Cys-368, thereby reinforcing the NQO1-IκBα interaction, possibly through NQO1-associated regulatory interfaces. This interaction inhibited NF-κB hyperactivation, suppressed glycolysis, and restored oxidative phosphorylation, thereby attenuating DON-induced pro-inflammatory microglial activation. Furthermore, NQO1 knockdown or Nrf2 knockout weakened the inhibitory effect of Raf on the NF-κB signaling pathway and inflammatory activation state of microglia. In conclusion, our findings revealed that Raf supplementation could efficiently alleviate DON exposure-induced neuroinflammation and neurobehavioral deficits by modulating NQO1/NF-κB-associated metabolic remodeling. These findings suggested that Raf may represent a potential therapeutic strategy against DON-induced neuroinflammation.