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.

Ferroptosis; Lutein; NRF2–HMOX2 Signaling Pathway; Neurons; Oxidative Stress; Parkinson's Disease.