Insight Into the Role of Ferroptosis in Non-neoplastic Neurological Diseases

Abstract

Ferroptosis is an iron-dependent form of cell death characterized by the accumulation of intracellular lipid reactive oxygen species (ROS). Ferroptosis is significantly different from other types of cell death including apoptosis, autophagy, and necrosis, both in morphology and biochemical characteristics. The mechanisms that are associated with ferroptosis include iron metabolism, lipid oxidation, and other pathophysiological changes. Ferroptosis inducers or inhibitors can influence its occurrence through different pathways. Ferroptosis was initially discovered in tumors, though recent studies have confirmed that it is also closely related to a variety of neurological diseases including neurodegenerative disease [Alzheimer's disease (AD), Parkinson's disease (PD), etc.] and stroke. This article reviews the definition and characteristics of ferroptosis, the potential mechanisms associated with its development, inducers/inhibitors, and its role in non-neoplastic neurological diseases. We hope to provide a theoretical basis and novel treatment strategies for the treatment of central nervous system diseases by targeting ferroptosis.

DHA and Its Elaborated Modulation of Antioxidant Defenses of the Brain: Implications in Aging and AD Neurodegeneration

“…Further, studies in GPx4BIKO mice (a mouse model with a conditional deletion in neurons of the forebrain of GPx4) have shown significant hippocampal neurodegeneration as well as deficits in spatial learning and memory function [162]. Similar results have been obtained using GPx4 inhibitors such as the Ras-selective lethal small molecule 3 (RSL3) [163]. Notably, maneuvers decreasing or abolishing adult brain GPx4 activity trigger a process known as ferroptosis, a type of programmed cell death dependent on iron and characterized by accumulation lipid peroxides secondary to decreased GPx4 activity (Figure 6) and often accompanied by ERK activation and neuroinflammation [67,164,165].…”

“…The exact pathway(s) underlying ferroptosis process have not been fully elucidated, but different reports have shown that AIF-mediated ferroptosis is initiated by a failure in glutathione antioxidant system defense, resulting in uncontrolled lipid peroxidation and ultimately cell death [164,165]. This occurs through two different (but not exclusive) mechanisms: (1) inhibition of x c − , the cysteine-glutamate antiporter, which limits the availability of cysteine and glutathione required for the function of GPx4, and (2) covalent binding of electrophilic lipoxygenase-mediated PUFA-derived inhibitors to the nucleophilic selenocysteine at the active site of GPx4 [164,165,168], as has been shown for the ferroptosis inducer (1S, 3R)-RSL3 [163,169,170].…”

Posttranslational Modifications in Ferroptosis

“…Due to the growing number of laboratories devoted to investigating the mechanisms and functions of ferroptosis, the research on ferroptosis is unprecedentedly prosperous. Recent studies have shown that ferroptosis plays a critical role in many diseases, including tumorigenesis, I/R injury, neurological disorders, and cardiovascular diseases [ 6 , 72 , 112 – 114 ]. At least three major pathways, namely, the glutathione-GPX4, FSP1-CoQ 10 , and GCH1-BH4 pathways, are involved in ferroptosis regulation [ 6 ].…”

Molecular mechanisms of ferroptosis and the potential therapeutic targets of ferroptosis signaling pathways for glioblastoma

“…Another finding shows that antioxidants reduce the content of milk iron and inhibit the production of iron-dependent lipid ROS. Transferrin expression is much higher in GBM than in other grades of glioma, and 8-hydroxydeoxyguanosine (8-OHd G), which indicates the oxidative stress level, showed the highest expression, thus indicating a positive correlation between the degree of tumor cell malignancy and the occurrence of cellular ferroptosis ( Lei et al, 2020 ; Garcia-Gomez et al, 2022 ). Tf is an 80 k Da glycoprotein found in plasma and represents an essential growth factor for cell proliferation ( Ratan, 2020 ; Zhao et al, 2022 ).…”