Molecular Mechanisms of Iron Mediated Programmed Cell Death and Its Roles in Eye Diseases

Abstract

Ferroptosis, a newly identified, iron-dependent type of programmed cell death, is active in several diseases, such as heart disease, brain damage, and cancer. Its main characteristics commonly involve excess iron accumulation, elevated lipid peroxides and reactive oxygen species, and reduced levels of glutathione and glutathione peroxidase 4 levels. The effects of ferroptosis in eye diseases cannot be underestimated, with ferroptosis becoming a research target in ocular disorders and emerging evidence from a series of in vivo and in vitro researches into ferroptosis revealing its role in eye conditions. However, no report provides comprehensive information on the pathophysiology of ferroptosis in eye diseases and its possible treatments. In the current review, we present an up-to-date overview of ferroptosis biology and its involvement in the pathological processes of ocular diseases. Furthermore, we pose several outstanding questions and areas for future research in this topic. We deem ferroptosis-associated cell death a pivotal new field of scientific study in ocular diseases and consider it a new therapeutic target in the treatment of some eye disorders.

Identification of potential ferroptosis-related biomarkers and a pharmacological compound in diabetic retinopathy based on machine learning and molecular docking

“…DR, characterized by ischemic microvascular disease of the retina and retinal neurodegeneration, is a highly specific complication of diabetes with complex multifactorial pathophysiology, which finally leads to visual impairment or blindness ( 29 ). Emerging evidence from a series of in vivo and in vitro studies revealed that ferroptosis, a new type of iron-dependent programmed cell death linking metabolism, disease, immune cells, and targeted therapy, is closely associated with the pathophysiological states of various ocular diseases, such as corneal alkali burn, glaucoma, age-related macular degeneration, and retinitis pigmentosa ( 6 , 30 – 32 ). Furthermore, targeting ferroptosis is a promising treatment for ocular diseases ( 6 , 31 ).…”

“…Emerging evidence from a series of in vivo and in vitro studies revealed that ferroptosis, a new type of iron-dependent programmed cell death linking metabolism, disease, immune cells, and targeted therapy, is closely associated with the pathophysiological states of various ocular diseases, such as corneal alkali burn, glaucoma, age-related macular degeneration, and retinitis pigmentosa ( 6 , 30 – 32 ). Furthermore, targeting ferroptosis is a promising treatment for ocular diseases ( 6 , 31 ). Some studies indicated that the inhibition of ferroptosis can alleviate cell death more effectively than the inhibition of apoptosis and necrosis in age-related macular degeneration ( 9 ).…”

“…Some studies indicated that the inhibition of ferroptosis can alleviate cell death more effectively than the inhibition of apoptosis and necrosis in age-related macular degeneration ( 9 ). Most recently, a growing number of studies indicate that ferroptosis may be closely involved in the development and progression of DR ( 6 ). Ferroptosis is involved in oxidative stress-induced RPE cell and HRCEC death under high-glucose conditions.…”

“…Ferroptosis is a recently identified type of cell death whose main characteristics are iron-dependent accretion of lipid reactive oxygen species and inhibition of the cystine/glutamate antiporter system Xc − , leading to decreased cystine uptake and glutathione (GSH) synthesis ( 5 ). Ferroptosis may fatally damage cells and result in certain eye diseases, such as glaucoma, retinal ischemia-reperfusion injury, and age-related macular degeneration ( 6 , 7 ). Recent evidence has revealed the role of ferroptosis in DR. Damage to retinal pigment epithelial (RPE) cells, the resulting destruction to the blood-retina barrier, and increased permeability of human retinal capillary endothelial cells (HRCECs) are key features in the occurrence and progression of DR.…”

Vitamin K and the Visual System: A Narrative Review

“…The implications of these findings with respect to VK and the EVS are significant. Zhang et al 2022 [205] provide a comprehensive review of ferroptotic biology and its involvement in major ocular diseases, and conclude that the effects of ferroptosis cannot be underestimated, deeming ferroptosis-related cell death to be a critical emerging field of study [205]. Yang et al 2022 [206] provide evidence in human primary RPE cells and in mice that the FSP1-CoQ10/VK-NADH pathways inhibit retinal ferroptotic pathology and may have a potential therapeutic role, providing supporting biochemical, histologic, and electroretinogram data [206].…”