Ferroptosis: past, present and future

Abstract

Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases.

Fig. 1

Ferroptosis has played important roles in multiple system diseases, such as nervous system diseases, heart diseases, liver diseases, gastrointestinal diseases, lung diseases, kidney diseases, pancreatic diseases, and so on.

Fig. 2. Regulatory pathways of ferroptosis.

The figure shows the regulatory pathways of ferroptosis, which can be roughly divided into three categories. The first one is regulated by GSH/GPX4 pathway, such as inhibition of system Xc-, sulfur transfer pathway, MVA pathway, glutamine pathway, and p53 regulatory axis. Second, the regulation mechanism of iron metabolism, such as the regulation of ATG5-ATG7-NCOA4 pathway and IREB2 related to ferritin metabolism, and the regulatory pathways of p62-Keap1-NRF2 and HSPB1 all have effects on iron. The third category is related pathways around lipid metabolism, such as P53-SAT1-ALOX15, ACSL4, LPCAT3, etc., which have effects on lipid regulation and ferroptosis. In addition, Erastin acts on mitochondria to induce ferroptosis. Also, recent studies have shown that the FSP1-CoQ10- NAD(P)H pathway exists as an independent parallel system that works cooperatively with GPX4 and glutathione to inhibit phospholipid peroxidation and ferroptosis.

Fig. 3

Hallmark contributions of ferroptosis.