Mechanisms of Ferroptosis and Relations With Regulated Cell Death: A Review

Abstract

Ferroptosis is a newly identified form of nonapoptotic regulated cell death (RCD) characterized by iron-dependent accumulation of lipid peroxides. It is morphologically and biochemically different from known types of cell death. Ferroptosis plays a vital role in the treatment of tumors, renal failure, and ischemia reperfusion injury (IRI). Inhibition of glutathione peroxidase 4 (GPX4), starvation of cysteine, and peroxidation of arachidonoyl (AA) trigger ferroptosis in the cells. Iron chelators, lipophilic antioxidants, and specific inhibitor prevent ferroptosis. Although massive researches have demonstrated the importance of ferroptosis in human, its mechanism is not really clear. In this review, we distanced ourselves from this confusion by dividing the mechanisms of ferroptosis into two aspects: processes that facilitate the formation of lipid peroxides and processes that suppress the reduction of lipid peroxides. At the same time, we summarize the relations between ferroptosis and several types of cell death.

Keywords: GPX4; RCD; ferroptosis; iron; lipid autoxidation; lipid peroxides.

FIGURE 1

Accumulation of lipid ROS: oxidation of lipid, lipid autoxidation, and Fenton reaction facilitate the generation of lipid ROS. The metabolism of amino acids suppresses the synthesis of GSH and the activity of GPX4, thus inhibiting the reduction of lipid ROS. The accumulation of lipid ROS leads to ferroptosis.

FIGURE 2

P53 and its dual effects on ferroptosis: P53 induces ferroptosis by inhibiting SLC7A11 like erastin; GSH is increased and xCT is inhibited in the cells treated with nutlin-3, a reagent that is used to stabilize p53. Cells treated with nutlin-3 show a delayed onset of ferroptosis in the presence of p21; In CRC, p53 activates DPP4 and transfers DPP4 to CRC nucleus from cytoplasm. The p53-DPP4 compound inhibits ferroptosis.

FIGURE 3

P62 and NRF2 in ferroptosis: NRF2 and p62 binds competitively to Keap1. Ferroptosis inducers facilitate the interaction between p62 and Keap1. This interaction inhibits Keap1. Inhibition of Keap1 prevents the binding between Keap1 and NRF2. Interaction of Keap1 and NRF2 triggers the degradation of NRF2. NRF2 mediated ferroptosis by regulating genes that involve in the metabolisms of iron and ROS. Thus, p62-Keap1-NRF2 pathway negatively mediated ferroptosis.