Kurarinone protects against neuronal ferroptosis and restores iron homeostasis through an ERα-associated NRF2/FTH1 pathway in cellular and animal models of Parkinson’s disease

Abstract Background Parkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra. Increasing evidence suggests that ferroptosis, an iron-dependent form of lipid peroxidation-driven cell death, contributes to PD pathogenesis. Kurarinone (KUR), a major prenylated flavonoid isolated from Sophora flavescens , has been reported to exert neuroprotective and anti-inflammatory effects, whereas its role in neuronal ferroptosis remains unclear. Results KUR markedly attenuated RSL3- and MPP + -induced neuronal injury in SH-SY5Y cells, accompanied by reduced intracellular labile iron accumulation and lipid peroxidation. KUR also partially restored the expression of the ferroptosis-associated proteins GPX4 and SLC7A11 following RSL3 or MPP + treatment. Network pharmacology analysis identified ESR1 , encoding estrogen receptor α (ERα), as a potential candidate target associated with KUR. KUR increased ERα expression and enhanced NRF2 expression and nuclear translocation, accompanied by increased FTH1 expression and reduced labile iron accumulation. Pharmacological inhibition or siRNA-mediated silencing of ESR1 attenuated KUR-associated activation of the NRF2/FTH1 axis and partially reversed its effects on iron accumulation and ferroptosis-related neuronal injury. Furthermore, in an MPTP-induced PD mouse model, KUR improved motor function and preserved tyrosine hydroxylase-positive dopaminergic neurons, accompanied by reduced iron deposition and lipid peroxidation in the midbrain. Conclusions These findings suggest that KUR alleviates ferroptosis-related neuronal injury by promoting iron sequestration through an ERα-associated NRF2/FTH1 signaling axis, supporting its potential as a candidate therapeutic strategy for ferroptosis-associated mechanisms in PD.