Lutein inhibits Parkinson's disease-induced ferroptosis of neuronal cells by activating NRF2 signaling.

Abstract

BACKGROUND: Ferroptosis in neuronal cells is closely related to the progression of Parkinson's disease (PD). Lutein is a naturally occurring carotenoid with neuroprotective properties, but the specific mechanism through which lutein regulates ferroptosis to protect PD neurons has not yet been fully elucidated. OBJECTIVE: This study aimed to investigate the regulatory effect of lutein on PD-induced ferroptosis in neuronal cells and its molecular mechanism. METHODS: An in vivo PD mouse model was established by the intraperitoneal injection of MPTP, and an in vitro model was established using the MPPinduction of SH-SY5Y cells. Motor function and neuronal injury were assessed by behavioral tests, H&E staining, TH immunohistochemistry, and Nissl staining. Ferroptosis-related indicators were detected using kits and Western blotting, and the interaction between Keap1 and NRF2 was validated by coimmunoprecipitation. RESULTS: Lutein treatment significantly improved pathological damage to the brain tissue of MPTP-induced PD mice, increased the number of TH-positive neurons, and reduced dyskinesia. Moreover, lutein could reduce the deposition of Feand the levels of MDA and ROS and upregulate the expression of SOD, GSH, SLC7A11 and GPX4 to inhibit the ferroptosis of neurons induced by MPTP/MPP. The effect was comparable to that of the ferroptosis inhibitor Fer-1. In terms of molecular mechanisms, MPPtreatment significantly increased the expression of Keap1 and decreased the expression of NRF2 and its downstream genes HO-1 and NQO1. Coimmunoprecipitation confirmed the interaction between Keap1 and NRF2. Overexpression of Keap1 attenuated the inhibitory effect of lutein on the ubiquitination and degradation of NRF2. Treatment with the NRF2 inhibitor ML385 or NRF2 knockdown reversed the inhibitory effects of lutein on ferroptosis. CONCLUSION: This study demonstrated that lutein can significantly activate NRF2 and its downstream antioxidant pathways by inhibiting Keap1-mediated ubiquitination and degradation of NRF2, effectively suppressing ferroptosis in neuronal cells and thereby exerting a neuroprotective effect.