The protective effect of biochanin A on LPS/TNF-α-induced PD models is exerted by regulating ferroptosis through the Sirt1/Nrf2/GPX4 signaling pathway.

Ferroptosis promotes the progression of Parkinson's disease (PD) through its unique regulatory pathways. Biochanin A (Bioch A) has long attracted the attention of researchers due to its neuroprotective effects. However, whether Bioch A can treat PD by inhibiting ferroptosis and the underlying mechanism remain unclear. This study aimed to investigate whether Bioch A exerts a neuroprotective effect on PD by activating the Sirt1/Nrf2/GPX4 signaling pathway to inhibit ferroptosis. Behaviors were evaluated by the open field and grip forced tests in mice. Immunofluorescence staining, lipid peroxidation assay, transmission electron microscopy (TEM), cell viability assay, and Western blot were used to detect pathological changes and the expression levels of ferroptosis-related proteins in mice and SH-SY5Y cells. The results of the study indicate that Bioch A exerts a neuroprotective effect by improving iron metabolism, and restoring the imbalance of the antioxidant system, and reducing the production of lipid peroxides, thereby inhibiting ferroptosis. In addition, mechanistic validation showed that under the intervention of ML385 and EX527, Bioch A still maintained the activation of the Sirt1/Nrf2/GPX4 signaling pathway, thereby significantly inhibiting ferroptosis in SH-SY5Y cells. Collectively, this study confirms that Bioch A exerts neuroprotective effects against PD by inhibiting ferroptosis through targeting the Sirt1/Nrf2/GPX4 signaling pathway, providing a novel targeted strategy and potential intervention approach for PD treatment.