Hypoxia-inducible factor-1 as targets for neuroprotection : from ferroptosis to Parkinson's disease.

Abstract

Parkinson's disease (PD) is a neurodegenerative disease characterized by motor paralysis, tremor,and cognitive impairment. Risk factors such as brain hypoxia caused by aging and abnormal expression of HIF-1α areconsidered to be key to the development of PD, including α-synuclein accumulation and ferroptosis. However, therelationship between HIF-1α signaling and ferroptosis in PD has not been elucidated. The stable expression of HIF-1αinhibits the pathological development of PD. Aging aggravates PD pathology by promoting α-synuclein accumulationand oxidative stress. The literature on lipid peroxidation, oxidative stress, iron metabolism and other key factors in Parkinson'sdisease in recent years was reviewed through a variety of literature search channels, such as PubMed and Elsevier. HIF-1α mediated ferroptosis through oxidative stress and GPX4-GSH system. HIF-1α mediates ferroptosisthrough Keap1-Nrf2-ARE, Grx3 and Grx4. HIF-1α mediates ferroptosis through iron metabolism. This article reviews the oxygen-dependent regulatory mechanism of HIF-1α and its role in cerebralhypoxia homeostasis. Studies in the past decade have shown that Hif-1α mediated ferroptosis is important in PD.HIF-1α has a dual role, depending on the degree of cellular hypoxia and the environment. The equilibrium complexityneeds to be explained, and the role of ferroptosis needs to be investigated. The literature shows that the stabilizationof HIF-1α with PHD inhibitors and the combination of antioxidants and iron chelators are potential therapeuticdirections. In the future, the optimal use time and dose of inhibitors should be studied to improve the efficacy.