Ferroptosis Explained: How Iron Drives a Distinct Form of Cell Death

For decades, biologists recognised a small number of ways a cell could die: a tidy, programmed shutdown called apoptosis, an uncontrolled bursting called necrosis, and a few others. In 2012, researchers described a different route, one that depends on iron and on a chain reaction that destroys the fats in a cell’s membranes. They called it ferroptosis.

In little more than a decade, ferroptosis has become one of the most active areas in cell biology. It links iron, oxidative stress, glutathione and NRF2, and it has been implicated in conditions from acute kidney injury to cancer. This guide explains what ferroptosis is, how cells defend against it, where it appears in disease, and what remains uncertain. Every key point is linked to its source.

In this guide: What ferroptosis is · How it was discovered · Why iron matters · How cells defend against it · The NRF2 connection · Ferroptosis in disease · Ferroptosis and cancer · What we still do not know · Common questions · References

What ferroptosis is

Every cell is wrapped in membranes built largely from fats called phospholipids. Some of these contain polyunsaturated fatty acids, which keep membranes flexible but are also easy to oxidise. When one of these fats is attacked, it can become a lipid peroxide, which attacks its neighbours in turn. If nothing stops the chain reaction, the membrane is damaged so badly that the cell dies.

A 2017 review in Cell describes ferroptosis as regulated cell death caused by the iron-dependent build-up of these lipid peroxides to lethal levels. The authors suggest it reflects an ancient vulnerability that comes with using polyunsaturated fats in membranes, and that cells have evolved several systems to defend against it [2].

Ferroptosis looks and behaves differently from other forms of cell death. It does not depend on the enzymes that drive apoptosis, and it can be blocked by compounds that stop lipid peroxidation or remove iron [1, 3].

How it was discovered

The name came from a 2012 paper in Cell by Scott Dixon, Brent Stockwell and colleagues at Columbia University. They were studying a compound called erastin, which kills certain cancer cells. They found that erastin triggered a form of death that depended on iron, but not on other metals, and that was distinct from apoptosis, necrosis and autophagy [1].

Erastin works by blocking a transporter known as system xc minus, which brings cystine into the cell. Cystine is needed to make cysteine and therefore glutathione. Without it, the cell’s defences against lipid peroxidation collapse [1]. The researchers also identified a compound, ferrostatin-1, that blocked this form of death, and noted that it also protected rat brain tissue from a related type of damage [1].

Why iron matters

Iron is essential for life. It carries oxygen in haemoglobin, helps mitochondria make energy and is needed to copy DNA. The body controls it tightly, through a hormone called hepcidin that manages iron levels in the blood, and through proteins inside cells that adjust how much iron is taken up and stored, as described in a 2010 review in Cell [4].

The reason for that control is that free iron is chemically reactive. In what is known as the Fenton reaction, iron reacts with hydrogen peroxide to produce highly reactive species, including the hydroxyl radical, that can damage almost any molecule [5]. Iron also activates some enzymes that help oxidise fats. In ferroptosis, this reactive iron helps drive the chain reaction of lipid peroxidation [2, 3].

How cells defend against it

GPX4 and glutathione. The central defence is an enzyme called glutathione peroxidase 4, or GPX4. In 2014, Brent Stockwell’s team reported in Cell that GPX4 is the key regulator of ferroptosis: it uses glutathione to convert lipid peroxides into harmless alcohols before they can spread [6]. Ferroptosis could be triggered either by draining glutathione or by blocking GPX4 directly [6]. Our guide to glutathione explains how cells make and recycle it.

The importance of GPX4 in living animals was shown the same year. In a study in Nature Cell Biology, switching off the GPX4 gene in adult mice caused acute kidney failure and death through ferroptosis, which a newly discovered ferroptosis blocker could prevent [7].

FSP1 and coenzyme Q10. Some cells survive even when GPX4 is blocked. In 2019, two teams reported in Nature that a protein they renamed ferroptosis suppressor protein 1, or FSP1, provides a second, independent line of defence [8, 9]. FSP1 works at the cell membrane, where it regenerates the reduced form of coenzyme Q10, which then traps the radicals that drive lipid peroxidation [9]. This finding helped explain why cancer cells vary so widely in their sensitivity to ferroptosis [8, 9].

The NRF2 connection

Many of the genes that protect against ferroptosis are switched on by NRF2, the master regulator of cellular defences. A 2019 review in Redox Biology describes how NRF2 controls genes involved in glutathione production, cystine import, iron storage and the removal of lipid peroxides, placing it at the centre of the cell’s anti-ferroptosis network [10]. Our guide to the NRF2 pathway explains this switch in detail.

The same review notes the double edge that runs through this field: NRF2 activity can protect healthy tissue from ferroptosis, but in some cancers it may help tumour cells resist treatments that aim to trigger it [10].

Ferroptosis in disease

Since 2012, ferroptosis has been implicated in a wide range of conditions, most of them involving tissue injury. A 2017 review lists degenerative brain diseases such as Alzheimer’s, Huntington’s and Parkinson’s, stroke, bleeding in the brain, traumatic brain injury, kidney degeneration and the damage that occurs when blood flow returns to an organ after a period without it, known as ischaemia-reperfusion injury [2].

The kidney has been one of the clearest examples. A 2014 study in the Proceedings of the National Academy of Sciences used live imaging in mice to show that ferroptosis drives the waves of cell death seen in kidney tubules after ischaemia and other forms of acute kidney injury, and that an improved ferroptosis blocker protected the kidneys [11].

Most of this evidence comes from cells and animal models. Showing that ferroptosis drives disease in people, and that blocking it helps, is still largely work in progress [3, 14].

Ferroptosis and cancer

Ferroptosis appears to be one of the body’s natural defences against cancer. A 2015 study in Nature showed that the tumour suppressor p53 can make cells more prone to ferroptosis by reducing cystine import, and that this activity contributes to its ability to suppress tumour growth in mice [12].

The immune system may use it too. A 2019 study in Nature reported that immune cells activated by cancer immunotherapy release a signal, interferon gamma, that reduces cystine uptake in tumour cells and makes them more vulnerable to ferroptosis, which contributed to the treatment’s effect in mouse models [13].

A 2021 review in Nature Reviews Molecular Cell Biology notes that some cancer cells that resist conventional therapy are particularly vulnerable to ferroptosis, which has made inducing it an attractive strategy [3]. At the same time, many tumours raise their defences, including glutathione and NRF2 activity, which may protect them [3, 10]. No cancer drug designed specifically to trigger ferroptosis has yet been approved.

What we still do not know

In a 2022 review marking ten years of ferroptosis research, Brent Stockwell set out the major open questions in the field [14]. Among them, researchers still lack a reliable marker to show that ferroptosis is happening in a human tissue, which makes it difficult to confirm its role in disease. It is not fully clear what the final step is that kills the cell once lipid peroxidation takes hold. And the normal, healthy functions of ferroptosis, if any, are only beginning to be explored [14].

It is also uncertain whether blocking or triggering ferroptosis can be done safely in people, given how many tissues depend on the same iron and antioxidant systems.

Common questions

What does ferroptosis mean?
The name combines ferrum, Latin for iron, with ptosis, Greek for falling, reflecting that it is a form of cell death that depends on iron [1].

How is ferroptosis different from apoptosis?
Apoptosis is a controlled shutdown run by specific enzymes. Ferroptosis is driven by iron-dependent oxidation of membrane fats and does not use the same machinery [1, 2].

What protects cells from ferroptosis?
The main defences are the enzyme GPX4, which uses glutathione to repair damaged fats [6], and a second system involving FSP1 and coenzyme Q10 [8, 9]. Many of the relevant genes are controlled by NRF2 [10].

Is ferroptosis good or bad?
Both, depending on context. It appears to contribute to tissue damage in injuries such as kidney failure [7, 11], while also helping to suppress some cancers [12, 13].

Can ferroptosis be treated or prevented?
Compounds that block or trigger ferroptosis work in cells and animals, but none is approved as a treatment, and human trials are at an early stage [3, 14].

Further reading: Redox signalling explained: how cells use reactive oxygen as a message.

Further reading: Sleep and cellular repair: what happens inside your cells while you sleep.

Further reading: Inflammation explained · Exercise and your cells

References

1. Dixon SJ, Lemberg KM, Lamprecht MR, et al. (2012). Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. https://doi.org/10.1016/j.cell.2012.03.042
2. Stockwell BR, Friedmann Angeli JP, Bayir H, et al. (2017). Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. https://doi.org/10.1016/j.cell.2017.09.021
3. Jiang X, Stockwell BR, Conrad M. (2021). Ferroptosis: mechanisms, biology and role in disease. Nature Reviews Molecular Cell Biology. https://doi.org/10.1038/s41580-020-00324-8
4. Hentze MW, Muckenthaler MU, Galy B, et al. (2010). Two to tango: regulation of mammalian iron metabolism. Cell. https://doi.org/10.1016/j.cell.2010.06.028
5. Winterbourn CC. (1995). Toxicity of iron and hydrogen peroxide: the Fenton reaction. Toxicology Letters. https://doi.org/10.1016/0378-4274(95)03532-X
6. Yang WS, SriRamaratnam R, Welsch ME, et al. (2014). Regulation of ferroptotic cancer cell death by GPX4. Cell. https://doi.org/10.1016/j.cell.2013.12.010
7. Friedmann Angeli JP, Schneider M, Proneth B, et al. (2014). Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nature Cell Biology. https://doi.org/10.1038/ncb3064
8. Doll S, Freitas FP, Shah R, et al. (2019). FSP1 is a glutathione-independent ferroptosis suppressor. Nature. https://doi.org/10.1038/s41586-019-1707-0
9. Bersuker K, Hendricks JM, Li Z, et al. (2019). The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. https://doi.org/10.1038/s41586-019-1705-2
10. Dodson M, Castro-Portuguez R, Zhang DD. (2019). NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biology. https://doi.org/10.1016/j.redox.2019.101107
11. Linkermann A, Skouta R, Himmerkus N, et al. (2014). Synchronized renal tubular cell death involves ferroptosis. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.1415518111
12. Jiang L, Kon N, Li T, et al. (2015). Ferroptosis as a p53-mediated activity during tumour suppression. Nature. https://doi.org/10.1038/nature14344
13. Wang W, Green M, Choi JE, et al. (2019). CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. https://doi.org/10.1038/s41586-019-1170-y
14. Stockwell BR. (2022). Ferroptosis turns 10: emerging mechanisms, physiological functions, and therapeutic applications. Cell. https://doi.org/10.1016/j.cell.2022.06.003

Redox News Today reports on published research for general interest. This guide is not medical advice. Last reviewed October 2026.