Lutein inhibits ferroptosis and reduces neuronal cell death induced by Parkinson's disease through the NRF2-HMOX2 signaling axis

Objective

This study aimed to investigate the role of lutein in the inhibition of ferroptosis in neurons induced by Parkinson's disease (PD) and the underlying molecular mechanisms.

Methods

PD animal and cellular models were established by the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice and treatment with 1-methyl-4-phenylpyridinium (MPP⁺) in SH-SY5Y cells. Behavioral tests, immunohistochemistry, and hematoxylin–eosin (HE) staining were employed to evaluate motor function and neuronal damage. Oxidative stress and ferroptosis-related markers were assessed using commercial assay kits and flow cytometry.

Results

Lutein treatment significantly alleviated MPTP-induced motor deficits in PD model mice and increased the number of tyrosine hydroxylase (TH)-positive neurons. Furthermore, lutein attenuated MPTP/MPP⁺-induced neuronal ferroptosis, as indicated by decreased Fe²⁺ and ACSL4 levels and elevated FTH1 and SLC7A11 expression—all of which were reversed by the ferroptosis activator erastin. Molecular docking and Western blot analyses demonstrated that lutein upregulated SOD1/2 and GPX1/2/3 expression. Notably, lutein treatment increased SOD and GSH levels while reducing MDA and ROS levels, indicating its neuroprotective role via antioxidant activation. Mechanistically, exposure to MPTP/MPP⁺ markedly suppressed NRF2 and HMOX2 expression, whereas lutein restored these levels; this protective effect was diminished by the NRF2 inhibitor ML385, which counteracted the suppression of oxidative stress and ferroptosis by lutein.

Conclusion

Lutein reduces dopaminergic neuronal death by promoting the expression of SOD1/2 and GPX1/2/3 and inhibiting PD ferroptosis through the activation of the NRF2–HMOX2 signaling pathway.