Evodiamine rescues lipopolysaccharide-induced cognitive impairment via C/EBP-β-COX2 axis-regulated neuroinflammation

Neuroinflammation is a key driver of neurological disorders. Evodiamine (EVO), an alkaloid from the traditional Chinese herb Evodia rutaecarpa, possesses potent biological activities, notably anticancer and anti-inflammatory effects. This study investigates EVO's potential to attenuate LPS-induced neuroinflammation, focusing on identifying its therapeutic targets and mechanisms of action. EVO treatment significantly improved mitochondrial function and reduced oxidative stress in LPS-stimulated BV₂ cells, while also lowering levels of pro-inflammatory factors (IL-6, NO, IL-1β) in brain organoids. In mice, EVO treatment alleviated behavioral abnormalities, especially in cognition and memory, and lowered hippocampal inflammation marker levels. To elucidate the critical mechanisms by which EVO exerts its anti-inflammatory effects, we analyzed LPS-induced inflammatory injury in BV₂ cells and used transcriptomics to investigate whether EVO modulates the C/EBP-β signaling pathway. Further validation using si-C/EBP-β confirmed EVO's regulatory effect on the C/EBP-β-COX2 axis, showing that knockdown significantly reduced pro-inflammatory factor expression, thereby providing neuroprotection. Moreover, molecular docking and dynamics simulations confirmed a stable interaction between EVO and C/EBP-β, supporting its role in attenuating LPS-induced neuroinflammation. In summary, these findings suggest that EVO regulates inflammation-related pathways by targeting the C/EBP-β-COX2 axis, offering neuroprotective benefits and mitigating neuroinflammatory responses.