Review | Published:

Ferroptosis: process and function

Cell Death and Differentiation volume 23, pages 369379 (2016) | Download Citation

Edited by M Piacentini

Abstract

Ferroptosis is a recently recognized form of regulated cell death. It is characterized morphologically by the presence of smaller than normal mitochondria with condensed mitochondrial membrane densities, reduction or vanishing of mitochondria crista, and outer mitochondrial membrane rupture. It can be induced by experimental compounds (e.g., erastin, Ras-selective lethal small molecule 3, and buthionine sulfoximine) or clinical drugs (e.g., sulfasalazine, sorafenib, and artesunate) in cancer cells and certain normal cells (e.g., kidney tubule cells, neurons, fibroblasts, and T cells). Activation of mitochondrial voltage-dependent anion channels and mitogen-activated protein kinases, upregulation of endoplasmic reticulum stress, and inhibition of cystine/glutamate antiporter is involved in the induction of ferroptosis. This process is characterized by the accumulation of lipid peroxidation products and lethal reactive oxygen species (ROS) derived from iron metabolism and can be pharmacologically inhibited by iron chelators (e.g., deferoxamine and desferrioxamine mesylate) and lipid peroxidation inhibitors (e.g., ferrostatin, liproxstatin, and zileuton). Glutathione peroxidase 4, heat shock protein beta-1, and nuclear factor erythroid 2-related factor 2 function as negative regulators of ferroptosis by limiting ROS production and reducing cellular iron uptake, respectively. In contrast, NADPH oxidase and p53 (especially acetylation-defective mutant p53) act as positive regulators of ferroptosis by promotion of ROS production and inhibition of expression of SLC7A11 (a specific light-chain subunit of the cystine/glutamate antiporter), respectively. Misregulated ferroptosis has been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, acute renal failure, drug-induced hepatotoxicity, hepatic and heart ischemia/reperfusion injury, and T-cell immunity. In this review, we summarize the regulation mechanisms and signaling pathways of ferroptosis and discuss the role of ferroptosis in disease.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , , , , , et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 2012; 149: 1060–1072.

  2. 2.

    , , , . Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 2003; 3: 285–296.

  3. 3.

    , . Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem Biol 2008; 15: 234–245.

  4. 4.

    , , , , , et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature 2007; 447: 864–868.

  5. 5.

    , , , , , et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 2014; 16: 1180–1191.

  6. 6.

    , , , , , et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 2014; 156: 317–331.

  7. 7.

    , , , , , et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. eLife 2014; 3: e02523.

  8. 8.

    , , , , . Ferroptosis is Involved in Acetaminophen Induced Cell Death. Pathol Oncol Res 2015; 21: 1115–1121.

  9. 9.

    , , , , , et al. Identification of simple compounds with microtubule-binding activity that inhibit cancer cell growth with high potency. ACS Med Chem Lett 2012; 3: 35–38.

  10. 10.

    , , , , , et al. Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg Med Chem Lett 2012; 22: 1822–1826.

  11. 11.

    , , , , . Effects of a new centrally acting muscle relaxant, NK433 (lanperisone hydrochloride) on spinal reflexes. Eur J Pharmacol 1997; 337: 175–187.

  12. 12.

    , , , , , et al. Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc Natl Acad Sci USA 2011; 108: 8773–8778.

  13. 13.

    , , , . Sulfasalazine, a potent suppressor of lymphoma growth by inhibition of the x(c)- cystine transporter: a new action for an old drug. Leukemia 2001; 15: 1633–1640.

  14. 14.

    , , , , , et al. The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett 2015; 356: 971–977.

  15. 15.

    , , , , , et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int J Cancer 2013; 133: 1732–1742.

  16. 16.

    , , , , , et al. Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res 2014; 34: 6417–6422.

  17. 17.

    , , , , , et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 2015 Sep 24. doi: 10.1002/hep.28251. [Epub ahead of print].

  18. 18.

    , , , , . Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience 2015; 2: 517–532.

  19. 19.

    , , , , , et al. Artemisinin derivatives induce iron-dependent cell death (ferroptosis) in tumor cells. Phytomedicine 2015; 22: 1045–1054.

  20. 20.

    , . The role of iron and reactive oxygen species in cell death. Nat Chem Biol 2014; 10: 9–17.

  21. 21.

    , , , , , et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol 2015; 10: 1604–1609.

  22. 22.

    , , , , , et al. Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc 2014; 136: 4551–4556.

  23. 23.

    , , , , , et al. The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents. Mol Cell Oncol 2015 May 26. doi:10.1080/23723556.2015.1054549. [Epub ahead of print].

  24. 24.

    , , , , . Functional model of metabolite gating by human voltage-dependent anion channel 2. Biochemistry 2011; 50: 3408–3410.

  25. 25.

    , , , , , et al. Voltage-dependent anion channels modulate mitochondrial metabolism in cancer cells: regulation by free tubulin and erastin. J Biol Chem 2013; 288: 11920–11929.

  26. 26.

    , , , , , . T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J Exp Med 2015; 212: 555–568.

  27. 27.

    , , , , , et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 2015; 520: 57–62.

  28. 28.

    , , , , , et al. Synchronized renal tubular cell death involves ferroptosis. Proc Natl Acad Sci USA 2014; 111: 16836–16841.

  29. 29.

    , , , , . Oncogenic RAS mutants confer resistance of RMS13 rhabdomyosarcoma cells to oxidative stress-induced ferroptotic cell death. Front Oncol 2015; 5: 131.

  30. 30.

    , , , , . Glutaminolysis and transferrin regulate ferroptosis. Mol Cell 2015; 59: 298–308.

  31. 31.

    , , , , , et al. Tumor suppression in the absence of p53-mediated cell-cycle arrest, apoptosis, and senescence. Cell 2012; 149: 1269–1283.

  32. 32.

    , , , , , et al. Murinedouble minute-2 prevents p53-overactivation-related cell death (podoptosis) of podocytes. J Am Soc Nephrol 2014; 26: 1513–1523.

  33. 33.

    , , , , . Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ 2015 Jul 17. doi: 10.1038/cdd.2015.93. [Epub ahead of print].

  34. 34.

    , , , . Ablation of ferroptosis inhibitor glutathione peroxidase 4 in neurons results in rapid motor neuron degeneration and paralysis. J Biol Chem 2015; 290: 28097–28106.

  35. 35.

    , , , , , et al. Glutathione peroxidase 4 prevents necroptosis in mouse erythroid precursors. Blood 2015 Oct 13. pii: blood-2015-06-654194. [Epub ahead of print].

  36. 36.

    , , , , , et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene 2015; 34: 5617–5625.

  37. 37.

    , , , . Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death. Oncotarget 2015; 6: 24393–24403.

  38. 38.

    , , , , , . A new microcellular cytotoxicity test based on calcein AM release. Hum Immunol 1993; 37: 264–270.

  39. 39.

    , . Sensitive colorimetric cytotoxicity measurement using alarmar blue. Oncol Rep 1995; 2: 59–61.

  40. 40.

    , , , , , et al. Trypan blue exclusion assay by flow cytometry. Braz J Med Biol Res 2014; 47: 307–315.

  41. 41.

    , , , , , . The 5-lipoxygenase inhibitor zileuton confers neuroprotection against glutamate oxidative damage by inhibiting ferroptosis. Biol Pharm Bull 2015; 38: 1234–1239.

  42. 42.

    , , , , , . Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-gamma-lyase function. Oncol Rep 2015; 33: 1465–1474.

  43. 43.

    , , , , , et al. Caspase-independent cell death is involved in the negative effect of EGF receptor inhibitors on cisplatin in non-small cell lung cancer cells. Clin Cancer Res 2013; 19: 845–854.

  44. 44.

    , , , , . Cellular protection using Flt3 and PI3Kalpha inhibitors demonstrates multiple mechanisms of oxidative glutamate toxicity. Nat Commun 2014; 5: 3672.

  45. 45.

    , , , , , et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 2009 16: 3–11.

  46. 46.

    , , , , , et al. Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ 2012 19: 107–120.

  47. 47.

    , , , , , et al. Classification of cell death: recommendations of the Nomenclature Committee on Cell Death. Cell Death Differ 2005; 12: 1463–1467.

Download references

Acknowledgements

We apologize to the researchers who were not referenced owing to space limitations. We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by the National Institutes of Health of the USA (R01CA160417 and R01GM115366 to DT), The National Natural Science Foundation of China (31171229 and U1132005 to XS), and a Science and Information Technology of Guangzhou Key Project (201508020258 and 201400000003/4 to XS).

Author information

Affiliations

  1. Department of Surgery, University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA

    • Y Xie
    • , W Hou
    • , X Song
    • , Y Yu
    • , R Kang
    •  & D Tang
  2. Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, China

    • Y Xie
    •  & J Huang
  3. Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China

    • X Sun
    •  & D Tang

Authors

  1. Search for Y Xie in:

  2. Search for W Hou in:

  3. Search for X Song in:

  4. Search for Y Yu in:

  5. Search for J Huang in:

  6. Search for X Sun in:

  7. Search for R Kang in:

  8. Search for D Tang in:

Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to R Kang or D Tang.

Glossary

AA

arachidonic acid

ACC1

acetyl-CoA carboxylase alpha

ACSF2

andacyl-CoA synthetase family member 2

ACSL4

acyl-CoA synthetase long-chain family member 4

AOA

aminooxyacetic acid

AKF

acute kidney failure

ATP5G3

ATP synthase F0 complex subunit C3

BSO

buthionine sulfoximine

BHT

butylated hydroxytoluene

CARS

cysteinyl-tRNA synthetase

CHAC1

cation transport regulator-like protein 1

COX-2

cyclooxygenase-2

CS

citrate synthase

CSSG

cysteine-glutathione disulfide

DAMP

damage-associated molecular pattern molecule

DMT1

divalent metal transporter 1

ER

endoplasmic reticulum

Fe3+

ferric iron

Fe2+

ferrous iron

FIN

ferroptosis-inducing agents

FLT-3

fms-like tyrosine kinase 3

FTH1

ferritin heavy chain 1

FTL

ferritin light chain

GPX4

glutathione peroxidase 4

GSH

glutathione

HMGB1

high mobility group box 1

HD

Huntington’s disease

HETE

hydroxyeicosatetraenoic acid

HO-1

heme oxygenase-1

HPETE

hydroperoxyeicosatetraenoic acid

HSF-1

heat shock factor-1

HSPB1

heat shock protein beta-1

HCC

hepatocellular carcinoma

IREB2

iron-responsive element-binding protein 2

JNK

c-Jun NH2-terminal kinase

Keap1

Kelch-like ECH-associated protein 1

LOX

lipoxygenases

LPCAT3

lysophosphatidylcholine acyltransferase 3

MAPK

mitogen-activated protein kinase

MDM2

murine double minute-2

MEFs

mouse embryonic fibroblasts

NADPH

nicotinamide adenine dinucleotide phosphate

NAPQI

N-acetyl-p-benzoquinone imine

NOX

NADPH oxidase

NRF2

nuclear factor erythroid 2-related factor 2

OLs

oligodendrocytes

PDAC

pancreatic ductal adenocarcinoma

PGSK

phen green SK

PKC

protein kinase C

PPP

pentose phosphate pathway

PTGS

prostaglandin-endoperoxide synthase

PUFAs

polyunsaturated fatty acids

PVL

periventricular leukomalacia

RCD

regulated cell death

ROS

reactive oxygen species

RPL8

ribosomal protein L8

RSLs

Ras-selective lethal small molecules

SCP2

sterol carrier protein 2

TFR1

transferrin receptor 1

TTC35

tetratricopeptide repeat domain 35

VDAC

mitochondrial voltage-dependent anion channel.

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/cdd.2015.158

Further reading