The Latest View on the Mechanism of Ferroptosis and Its Research Progress in Spinal Cord Injury

Abstract

Ferroptosis is a recently identified nonapoptotic form of cell death whose major markers are iron dependence and accumulation of lipid reactive oxygen species, accompanied by morphological changes such as shrunken mitochondria and increased membrane density. It appears to contribute to the death of tumors, ischemia-reperfusion, acute renal failure, and nervous system diseases, among others. The generative mechanism of ferroptosis includes iron overloading, lipid peroxidation, and downstream execution, while the regulatory mechanism involves the glutathione/glutathione peroxidase 4 pathway, as well as the mevalonate pathway and the transsulfuration pathway. In-depth research has continuously developed and enriched knowledge on the mechanism by which ferroptosis occurs. In recent years, reports of the noninterchangeable role played by selenium in glutathione peroxidase 4 and its function in suppressing ferroptosis and the discovery of ferroptosis suppressor protein 1, identified as a ferroptosis resistance factor parallel to the glutathione peroxidase 4 pathway, have expanded and deepened our understanding of the mechanism by which ferroptosis works. Ferroptosis has been reported in spinal cord injury animal model experiments, and the inhibition of ferroptosis could promote the recovery of neurological function. Here, we review the latest studies on mechanism by which ferroptosis occurs, focusing on the ferroptosis execution and the contents related to selenium and ferroptosis suppressor protein 1. In addition, we summarize the current research status of ferroptosis in spinal cord injury. The aim of this review is to better understand the mechanisms by which ferroptosis occurs and its role in the pathophysiological process of spinal cord injury, so as to provide a new idea and frame of reference for further exploration.

Targeting SLC3A2 subunit of system XC− is essential for m6A reader YTHDC2 to be an endogenous ferroptosis inducer in lung adenocarcinoma

“…Cell detachment and overt cell death were also observed began at that time (Figure . 1C). Ferroptosis is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities [35,36], induction of YTHDC2 following treating with 1.6 µM Dox for 24h caused similar results in H1299 and H441 cells (Supplementary Figure . 1B-C).…”

Zinc attenuates ferroptosis and promotes functional recovery in contusion spinal cord injury by activating Nrf2/GPX4 defense pathway

“…A large number of blood cells and hemoglobin are destroyed and degraded, resulting in a sharp increase in the level of iron ions in the injured area. Additionally, the tissue at the injured site is necrotic and produces many reactive oxygen species and oxidative stress products 7‐10 . The content of saturated fatty acids is very high.…”

“…Additionally, the tissue at the injured site is necrotic and produces many reactive oxygen species and oxidative stress products. 7 , 8 , 9 , 10 The content of saturated fatty acids is very high. Finally, due to iron and lipid supersaturation, the production of lipid peroxides suddenly increases, and iron catalyzes enzyme‐mediated programmed cell death.…”

Oxidative Stress Triggers Defective Autophagy in Endothelial Cells: Role in Atherothrombosis Development

“…Ferroptosis is an iron-dependent form of non-apoptotic cell death, marked by a requirement for the accumulation of lipid ROS and characterized by typical morphological, biochemical, and genetic features [ 161 ]. Several studies have enriched the knowledge on how ferroptosis occurs, outlining both the generative mechanism involving iron overload and lipid peroxidation, considered to be the two central biochemical events, and the regulatory mechanisms including the ever-expanding number of pathways that modulate ferroptosis, such as the glutathione/glutathione peroxidase 4 (GPX4) pathway, mevalonate pathway, trans-sulfuration pathway, RAS-BRAF-MAP2K/MEK pathway, and HSF1-HSPB1-PRKC pathway [ 162 , 163 , 164 , 165 ].…”

“…Moreover, once an imbalance occurs between the ROS induced by iron enrichment and the antioxidant system, lipid peroxidation can occur, which damages the plasma membrane and induces iron death. The large concentration of Fe 2+ that collects in the cytoplasm induces lipid hydroperoxide to generate toxic lipid ROS which, in turn, target PUFAs by catching electrons near the PUFAs, triggering a vicious reaction cycle of lipid oxidation and causing more severe oxidative damage [ 162 , 163 ]. Among the several pathways involved, ferroptosis can be induced by erastin, which inhibits the membrane-bound cystine/glutamate antiporter XC-.…”