Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases.

Xiaohua Song,Dingxin Long

doi:10.3389/fnins.2020.00267

Abstract

Ferroptosis is a kind of regulated cell death (RCD) caused by the redox state disorder of intracellular microenvironment controlled by glutathione (GSH) peroxidase 4 (GPX4), which is inhibited by iron chelators and lipophilic antioxidants. In addition to classical regulatory mechanisms, new regulatory factors for ferroptosis have been discovered in recent years, such as the P53 pathway, the activating transcription factor (ATF)3/4 pathway, Beclin 1 (BECN1) pathway, and some non-coding RNA. Ferroptosis is closely related to cancer treatment, neurodegenerative diseases, ischemia–reperfusion of organ, neurotoxicity, and others, in particular, in the field of neurodegenerative diseases treatment has aroused people’s interest. The nuclear factor E2 related factor 2 (Nrf2/NFE2L2) has been proved to play a key role in neurodegenerative disease treatment and ferroptosis regulation. Ferroptosis promotes the progression of neurodegenerative diseases, while the expression of Nrf2 and its target genes (Ho-1, Nqo-1, and Trx) has been declined with aging; therefore, there is still insufficient evidence for ferroptosis and Nrf2 regulatory networks in the field of neurodegenerative diseases. In this review, we will provide a brief overview of ferroptosis regulatory mechanisms, as well as an emphasis on the mechanism of Nrf2 regulating ferroptosis. We also highlight the role of ferroptosis and Nrf2 during the process of neurodegenerative diseases and investigate a theoretical basis for further research on the relationship between Nrf2 and ferroptosis in the process of neurodegenerative diseases treatment.

Highlights

Programed cell death is critical to all aspects of mammalian growth and development, homeostatic regulation, and disease control and is closely integrated with other biological processes to sustain life
Once the body is in oxidative stress, or if there are a large number of electrophiles or cytotoxic agents, Nrf2 is released from the Kelch-like ECH-related protein 1 (Keap1) binding site and rapidly transferred to the nucleus, subsequently interacting with the antioxidant response element (ARE) in the promoter region of the target gene and activates the transcriptional pathway to balance oxidative stress and maintain cellular redox homeostasis (Zhang, 2006)
Ferroptosis is initiated by severe lipid peroxidation relying on reactive oxygen species (ROS) generation and intracellular iron overload, but many of its physiological effects are yet to be defined

Summary

Introduction

Programed cell death is critical to all aspects of mammalian growth and development, homeostatic regulation, and disease control and is closely integrated with other biological processes to sustain life. In the field of neurodegenerative diseases, there is insufficient research evidence to show that Nrf2 can protect nerve and its related regulatory factors by regulating the mechanism of ferroptosis.

Results

Conclusion