DDX17 acts as a target of Buddlejasaponin IVb ameliorating dopaminergic neuron iron metabolism dysregulation in Parkinson's disease.

Identifying novel targets that ameliorating dopaminergic neuron iron metabolism dysregulation may provide potential therapeutic strategies for Parkinson's disease (PD). Buddlejasaponin IVb (BJP-IVb) is the first natural product that can ameliorate iron regulatory protein 2 (IRP2)-mediated iron metabolism dysregulation in dopaminergic neuron to suppress PD. BJP-IVb may exert this bioactivity through novel target. However, the pharmacological target of BJP-IVb is unclear. This study aimed to discovery the potential novel target of BJP-IVb ameliorating dopaminergic neuron iron metabolism dysregulation in PD. BJP-IVb probe (BJP-IVb-P) were synthesized to identify the potential novel target by affinity-based protein profiling. The expression of DEAD-box helicase 17 (DDX17) was knocked down in vitro and in vivo to prove the potential novel target of BJP-IVb is DDX17. We proved that BJP-IVb could directly bind to DDX17. Dopaminergic neurons exhibit an elevated expression of DDX17 in PD. Dopaminergic neuron iron metabolism dysregulation and Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5) signaling pathway activation in PD could be alleviated by the knockdown of DDX17 in vitro and in vivo. The inhibitory effect of BJP-IVb on dopaminergic neuron iron metabolism dysregulation and JAK2-STAT5 signaling pathway activation in PD could be abolished by the knockdown of DDX17 in vitro and in vivo. This study first proved that DDX17 is a pharmacological target for ameliorating dopaminergic neuron iron metabolism dysregulation in PD, and BJP-IVb ameliorates dopaminergic neuron iron metabolism dysregulation by targeting DDX17.