Ferroptosis: Death by Lipid Peroxidation

Abstract

Ferroptosis is a regulated form of cell death driven by loss of activity of the lipid repair enzyme glutathione peroxidase 4 (GPX4) and subsequent accumulation of lipid-based reactive oxygen species, particularly lipid hydroperoxides. This form of iron-dependent cell death is genetically, biochemically, and morphologically distinct from other cell death modalities, including apoptosis, unregulated necrosis, and necroptosis. Ferroptosis is regulated by specific pathways and is involved in diverse biological contexts. Here, we summarize the discovery of ferroptosis, the mechanism of ferroptosis regulation, and its increasingly appreciated relevance to both normal and pathological physiology.

Ferredoxin reductase is critical for p53-dependent tumor suppression via iron regulatory protein 2

“…As a major regulator of iron homeostasis and a mediator of ROS-mediated apoptosis (Hwang et al 2001;Liu and Chen 2002), FDXR may play a role in p53-dependent ferroptosis (Jiang et al 2015), which is characterized by lipid peroxidation, generation of lipid-based ROS, and its dependency on iron (Yang and Stockwell 2016). To test this, we examined whether FDXR modulates the extent of ferroptosis induced by RSL3 and Erastin.…”

An Overview of Pathways of Regulated Necrosis in Acute Kidney Injury

“…45,46 Indeed, all known initiators of ferroptosis to date either suppress the systems that are needed for generation of intracellular glutathione or inhibit GPX4 activity. 47 During ferroptosis initiation, cystine uptake is abolished by inhibition of the function of the cystine/glutamate antiporter system X C -. 48 Iron-loaden transferrin internalization via the transferrin receptor in the context of cystine deprivation was described as a trigger for ferroptosis.…”

Ferroptosis is an autophagic cell death process

“…While apoptosis is the best-studied form of programmed cell death, recent studies demonstrate that there are also programmed cell death processes that are not apoptosis [4][5][6][7]. For example, necroptosis and ferroptosis are two distinct regulated necrosis pathways that are under precise genetic control and may function under diverse physiological and pathological contexts [8][9][10].…”

“…Ferroptosis is emerging as a new form of programmed necrosis whose execution requires the accumulation of cellular reactive oxygen species (ROS) in an iron-dependent manner [8]. Synthetic small-molecule compound erastin can trigger ferroptosis by inhibiting the activity of cystine-glutamate antiporter (system X c -), leading to the depletion of glutathione (GSH), the major cellular antioxidant whose synthesis requires cysteine [11,12].…”