HSPA4 restrains transferrin in dopaminergic neurons to attenuate ferroptosis in a Parkinson’s disease model

Heat shock protein A4 (HSPA4) is a molecular chaperone belonging to the heat shock protein 70 (HSP70) family. This study aims to investigate the antiferroptotic effects of HSPA4 in a Parkinson's disease (PD) model and explore the underlying mechanisms. Here we show that HSPA4 overexpression reduces ferroptosis in erastin-treated SH-SY5Y cells and primary dopaminergic neurons, while HSPA4 knockdown exacerbates ferroptosis. In MPTP-induced PD model mice, HSPA4 rectifies behavioral defects, prevents the loss of dopaminergic neurons, and alleviates ferroptosis. Mechanistically, HSPA4 interacts with transferrin in the cytoplasm and inhibits its export from the cell. Consequently, extracellular iron cannot be transported into cells due to a lack of transferrin, thereby attenuating ferroptosis in dopaminergic neurons and slowing PD progression. By restraining transferrin in dopaminergic neurons, HSPA4 reduces ferroptosis and alleviates parkinsonism in a PD mouse model. Therefore, HSPA4 might present a potential therapeutic target for the development of PD treatments. HSPA4 mitigates ferroptosis in Parkinson's disease models by binding transferrin and preventing iron uptake, protecting dopaminergic neurons and improving motor function, suggesting its potential as a therapeutic target.