Kurarinone curbs neuronal ferroptosis via ERα–NRF2/FTH1 pathway in Parkinson’s models

Kurarinone, a prenylated flavonoid isolated from the plant Sophora flavescens, protected dopaminergic neurons against ferroptosis in cellular and animal models of Parkinson’s disease, according to a research article published in Biological Research on 28 October 2026. The compound acted by restoring iron homeostasis through an ERα-associated NRF2/FTH1 signaling axis, a mechanism the authors propose as a candidate therapeutic strategy for ferroptosis-associated processes in the disease.

Parkinson’s disease 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 the disease’s pathogenesis. Although kurarinone had previously been reported to exert neuroprotective and anti-inflammatory effects, its role in neuronal ferroptosis remained unclear before this study.

In laboratory experiments, kurarinone markedly attenuated neuronal injury in SH-SY5Y cells induced by two ferroptosis-relevant insults: RSL3, a ferroptosis inducer, and MPP+, a toxin widely used to model parkinsonian damage. The treatment was accompanied by reduced intracellular labile iron accumulation and reduced lipid peroxidation, the two hallmark features of ferroptotic cell death.

The compound also partially restored the expression of the ferroptosis-associated proteins GPX4 and SLC7A11 following RSL3 or MPP+ treatment, indicating that kurarinone acts on core components of the cellular defense system against lipid peroxidation.

To identify molecular targets, the researchers performed network pharmacology analysis, which flagged ESR1, the gene encoding estrogen receptor α (ERα), as a potential candidate target associated with kurarinone. Subsequent experiments showed that kurarinone increased ERα expression and enhanced the expression and nuclear translocation of NRF2, a master regulator of antioxidant responses. These changes were accompanied by increased expression of FTH1, the ferritin heavy chain responsible for sequestering iron, and by reduced labile iron accumulation in the cells.

The link between ERα and the downstream pathway was tested directly. Pharmacological inhibition of ESR1 or siRNA-mediated silencing of the gene attenuated kurarinone-associated activation of the NRF2/FTH1 axis and partially reversed the compound’s effects on iron accumulation and ferroptosis-related neuronal injury. This places ERα upstream of the NRF2/FTH1 mechanism through which kurarinone appears to promote iron sequestration.

The findings were extended to an animal model. In mice with MPTP-induced Parkinson’s disease, kurarinone improved motor function and preserved tyrosine hydroxylase-positive dopaminergic neurons in the midbrain. Biochemical analysis of the same brain region showed reduced iron deposition and reduced lipid peroxidation, mirroring the cellular results and connecting the iron-sequestration mechanism to preserved neuronal populations and motor behavior in vivo.

The authors conclude that kurarinone alleviates ferroptosis-related neuronal injury by promoting iron sequestration through the ERα-associated NRF2/FTH1 signaling axis. They frame the compound as a potential candidate therapeutic strategy for ferroptosis-associated mechanisms in Parkinson’s disease. As with all preclinical work, the results come from cell culture and a toxin-induced mouse model, and the study is an early-access, peer-reviewed accepted article whose final version of record is pending; translating the ERα–NRF2/FTH1 mechanism into clinical benefit for patients will require further research.

Subject of Research: Neuroprotective effects of kurarinone on ferroptosis and iron homeostasis in Parkinson's disease models

Article Title: 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

Article References: Chang, X., Wang, Y.-X., Su, Y., Ma, J.-J., & Wu, J. (2026). 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. Biological Research. https://doi.org/10.1186/s40659-026-00739-1

Image Credits: AI Generated

DOI: 10.1186/s40659-026-00739-1

Keywords: kurarinone, ferroptosis, Parkinson's disease, iron homeostasis, ERα, NRF2, FTH1, SH-SY5Y cells, MPTP mouse model, Sophora flavescens, lipid peroxidation, dopaminergic neurons