Cover Story：Reactive oxygen species (ROS) and NO free radicals generated from oxidative stress play an important role in the pathogenesis of neurodegenerative disease and cardiovascular and cerebrovascular diseases. Excessive NO production can cause free radical damage and induce neuron death. As one of the traditional Chinese medicine, Emodin have valuable and widely clinical applications. Recently, Emodin has been reported to have antioxidant, immunomodulatory, antibacterial, anti-inflamatory functions etc. FOXO1 is a vital member of the Forkhead family of transcription factors known to regulate the transcription of genes involved in cell cycle arrest, DNA repair in response to oxidative stress or apoptosis. However, it is unclear how the NO effect on FOXO1. In this study, we observed vital role of FOXO1 dependent transcriptional activation on neuronal death in response to Nitric oxide over-production. We found that NO donor GSNO or L-Arginine significantly increased the FOXO1 transcriptional activity, which induce the FOXO1 downstream proapoptotic genes (FasL, Bim) expression and finally induce neuronal death. In addition, we screen natural Chinese herb extracts targets to regulating FOXO1 activity. Emodin shows dramatically effect in suppression of FOXO1 transcription activity and protein levels. What’s more, Emodin can attenuate neuronal death induced by L-Arg. The current study first demonstrate that Nitric Oxide could regulate FOXO1 transcriptional activity to damage neuronal cell, which will benefit to deep understanding the neurotoxicity of NO free radical. Secondly, by Chinese herb extracts and antioxidants screen, we identified Emodin as one FOXO1 activity modulator which can attenuate neurotoxicity induced by NO. The current study will also provide a new insight for explaining the mechanisms of pathology of neurodegenerative disease and neuroprotective effects of Emodin.