Ferroptosis: mechanisms and links with diseases

Abstract

Ferroptosis is an iron-dependent cell death, which is different from apoptosis, necrosis, autophagy, and other forms of cell death. The process of ferroptotic cell death is defined by the accumulation of lethal lipid species derived from the peroxidation of lipids, which can be prevented by iron chelators (e.g., deferiprone, deferoxamine) and small lipophilic antioxidants (e.g., ferrostatin, liproxstatin). This review summarizes current knowledge about the regulatory mechanism of ferroptosis and its association with several pathways, including iron, lipid, and cysteine metabolism. We have further discussed the contribution of ferroptosis to the pathogenesis of several diseases such as cancer, ischemia/reperfusion, and various neurodegenerative diseases (e.g., Alzheimer's disease and Parkinson's disease), and evaluated the therapeutic applications of ferroptosis inhibitors in clinics.

Fig. 1. Timeline diagram depicting essential discoveries in the field of ferroptosis research.

The discovery of ferroptosis starts with identification of system xCT, which was published in 1980. However, the term ‘ferroptosis' was only named in 2012.

Fig. 2. Schematic description of the signaling pathway of ferroptosis.

The indicated pathways control ferroptosis sensitivity via lipid ROS generation. Phosphatidylethanolamines (PE); phospholipid (PL-H); phospholipid alkoxyl radical (PL-O·); phospholipid peroxyl radical (PL-OO·); phospholipid hydroperoxide (PL-OOH); transferrin (TF). The symbols used in the figure have been marked with names of the biomolecules.

Fig. 3. Overview of the anti-ferroptosis pathway.

Schematic description of the two defense mechanisms identified in ferroptosis, the GSH-dependent GPx4 pathway, and the NADPH-dependent FSP1 pathway. Glutamine (Gln); glutamate (Glu); cysteine (Cys); glycine (Gly); glutathione-disulfide reductase (GSR); stimulating proteins 1 and 3 (SP1/3); nuclear factor Y (NF-Y); cAMP-response element modulator-tau (CREM-tau); early growth response protein 1 (EGR1); nuclear factor κB (NF-κB); sterol regulatory-binding element 1 (SREBP1).

Fig. 4. Iron, ROS, ferroptosis, and ischemia-reperfusion injury.

The relationships between iron, ROS, and ferroptosis in ischemia/reperfusion has been illustrated, where ferroptosis may be a result of accumulated ROS, induced by impaired iron export. Iron chelators, anti-oxidants, and inhibitors of ferroptosis may prevent the toxic reaction.