The role of ferroptosis in central nervous system damage diseases

Abstract

Ferroptosis is a form of cell death, i.e., programmed cell death characterized by lipid peroxidation and iron dependence, which has unique morphological and biochemical properties. This unique mode of cell death is driven by iron-dependent phospholipid peroxidation and regulated by multiple cell metabolic pathways, including redox homeostasis, iron metabolism, mitochondrial activity, and the metabolism of amino acids, lipids, and sugars. Many organ injuries and degenerative pathologies are caused by ferroptosis. Ferroptosis is closely related to central nervous system injury diseases and is currently an important topic of research globally. This research examined the relationships between ferroptosis and the occurrence and treatment of central nervous system injury diseases. Additionally, ferroptosis was assessed from the aspect of theory proposal, mechanism of action, and related signaling pathways per recent research. This review provides a relevant theoretical basis for further research on this theory, the prospect of its development, and the prevention and treatment of such diseases.

Keywords: Ferroptosis; GPX4; Nerve damage; Redox.

Figure 1. GPX4 as a key linker in the development of ferroptosis.

GPX4 has been a key linker in the development of ferroptosis. First, GPX4 is an essential inhibitor of phospholipid peroxidation, together with the damage of mitochondria to contribute to the development of ferroptosis. In addition, the oxidized form of cysteine (Cystine) also counteracts ferroptosis by promoting the activity of GSH/GPX4. Furthermore, GPX4 induced ferroptosis can be influenced by environmental stress and intracellular and intercellular signal transport events which impact ROS levels, cellular metabolism and the level of Iron. In-depth studies have revealed that the deficiency of GPX4 can affect lipid peroxidation dependence. Also, Selenium/PUFA-PLs and scavenging superoxide affect the GPX4 induced ferroptosis. In addition, CoQ10 serves as a vital component of mitochondria and also inhibits lipid peroxidation outside the mitochondria. Consequently, the depletion of CoQ10 renders cells more susceptible to ferroptosis.

Figure 2. Hippo-YAP signaling pathway contributes to the occurrence of ferroptosis.

The effect of the Hippo-YAP pathway on ferroptosis in epithelial cells is regulated by e-calmodulin-mediated cell–cell contact. This contact inhibits the expression of melin, leading to the activation of the Hippo signaling pathway through the NF2 gene. Consequently, the YAP activity is suppressed. The Hippo-YAP pathway encompasses ACSL4, TFR1, and other possible genes that act as regulatory factors for ferroptosis. Notably, ASCL4 can further contribute to the activation of PUFA-PLs and PLOOH. The activity of the Hippo pathway performs a crucial function in the occurrence of ferroptosis, and heightened susceptibility to Hippo will increase the sensitivity of ferroptosis.