In LPS/TNF-α-induced mouse and SH-SY5Y cell PD models, biochanin A reduced lipid peroxidation, improved iron and antioxidant balance, and rescued behavioral and cellular deficits by inhibiting ferroptosis via the Sirt1/Nrf2/GPX4 signaling axis, with pathway involvement probed using ML385 and EX527.

Provides a mechanistically actionable lead (biochanin A) that targets ferroptosis through Sirt1–Nrf2–GPX4—an emerging PD-relevant pathway—making it a promising candidate for translational follow-up though it requires validation in classic PD models, BBB/PK and safety studies.

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. Behavior was evaluated by the open field and grip force 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 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.