Ferroptosis

Ferroptosis is a form of regulated cell death, distinct from apoptosis, necroptosis and autophagy. It is an iron-dependent process that results from the loss of glutathione peroxidase 4 (GPX4) activity, leading to accumulation of lipid peroxidation products and reactive oxygen species (ROS).

Products
Background
Literature
Pathways

Inhibitors

Cat No Product Name / Activity
1761 Baicalein
Inhibits ferroptosis; 5- and 1-lipoxygenase inhibitor
3003 Coenzyme Q10
Inhibits ferroptosis; antioxidant
0970 Cycloheximide
Inhibitor of ferroptosis; inhbits protein synthesis
5245 Ebselen
Inhibitor of ferroptosis; glutathione peroxidase mimic
5180 Ferrostatin 1
Selective inhibitor of erastin induced ferroptosis
3002 Idebenone
Inhibits ferroptosis; antioxidant and neuroprotective agent
2850 PD 146176
Inhibits ferroptosis; selective 15-lipoxygenase inhibitor
6002 Trolox
Inhibitor of ferroptosis; antioxidant
3308 Zileuton
Inhibits ferroptosis; 5-LOX inhibitor

Activators

Cat No Product Name / Activity
5449 Erastin
Ferroptosis activator; also mitochondrial VDAC modulator
6280 FIN 56
Ferroptosis activator
0218 L-Glutamic acid
Induces ferroptosis; endogenous, non-selective agonist
6118 1S,3R-RSL3
Induces ferroptosis; inhibits glutathione peroxidase 4 (GPX4)
1965 Simvastatin
Induces ferroptosis; also HMG-CoA reductase inhibitor
4935 Sulfasalazine
Ferroptosis inducer; cystine-glutamate antiporter inhibitor and inhibitor of NF-κB activation

Ferroptosis is a form of regulated cell death, distinct from apoptosis, necroptosis and autophagy. It is an iron-dependent process that results from the loss of glutathione peroxidase 4 (GPX4) activity, leading to accumulation of lipid peroxidation products and reactive oxygen species (ROS).

GPX4 is a selenoprotein that reduces hydrogen peroxide and lipid peroxides, while converting reduced glutathione (GSH) to its oxidized form; oxidized glutathione (glutathione disulfide) is recycled by glutathione reductase and NADPH/H+. Depletion of GSH leads to the inactivation of GPX4 with the resultant accumulation of ROS from lipid peroxidation and subsequent ferroptosis. GPX4 inactivation also causes depletion of arachidonic acid and polyunsaturated fatty acids and this also promotes ferroptosis.


Molecular Pathways of Ferroptosis Regulation

Molecular Pathways of Ferroptosis Regulation

Figure 1: Molecular Pathways of Ferroptosis Regulation. DMT1, Divalent metal transporter 1; Glu, Glutamate; GPX4, Glutathione peroxidase 4; GSH, Glutathione; HMG-CoA, 3-hydroxy-3-methyl-glutaryl-CoA reductase; IPP, Isopentenyl pyrophosphate; ROS, Reactive oxygen species; Se, Selenocysteine; System xc-, glutamate/cystine antiporter; TFR1, membrane protein transferrin receptor 1.

Adapted from Yang and Stockwell (2016) Trends Cell Biol. 26 165.


The mevalonate pathway is an important regulator of ferroptosis, as the synthesis of selenoproteins, such as GPX4, is dependent on isopentenyl pyrophosphate, a product of the mevalonate pathway. Isopentenyl pyrophosphate acts as a donor in the incorporation of selenocysteine into selenoproteins by the enzyme tRNA isopentenyl transferase. The glutamate/cysteine antiporter (system Xc-) is also an important regulator of ferroptosis. Inhibition of this transporter, by increased extracellular glutamate for example, depletes the intracellular pool of cysteine, which is a precursor of glutathione synthesis. This in turn depletes glutathione leading to inhibition of GPX4. The MAPK pathway may also have role in ferroptosis regulation.

While iron is a requirement for ferroptosis, its role in the process is not fully understood. It has been proposed that iron-containing enzymes associated with lipid redox regulation are activated during ferroptosis. Excessive iron contributes to ferroptosis, while iron chelators inhibit Erastin-induced ferroptosis.

Ferroptotic cells appear rounded, with no rupture of cell membranes. Mitochondria are smaller than normal, have dense mitochondrial membranes and lack cristae, while the nucleus appears normal. Ferroptosis is involved in many physiological and pathological processes including cancer cell death, neurotoxicity, neurodegenerative disease, acute kidney disease and T-cell immunity, among others. Inhibition of ferroptosis therefore offers a potential therapeutic approach for a variety of conditions.

Literature for Ferroptosis

Tocris offers the following scientific literature for Ferroptosis to showcase our products. We invite you to request* or download your copy today!

*Please note that Tocris will only send literature to established scientific business / institute addresses.


Cancer

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Autophagy

Autophagy Scientific Review

Written by Patricia Boya and Patrice Codogno, this review summarizes the molecular mechanisms, physiology and pathology of autophagy. The role of autophagy in cell death and its links to disease are also discussed. Compounds available from Tocris are listed.

MAPK Signaling

MAPK Signaling Scientific Review

MAP kinase signaling is integral to the regulation of numerous cellular processes such as proliferation and differentiation, and as a result is an important focus of cancer and immunology research. Updated for 2016, this review discusses the regulation of the MAPK pathway and properties of MAPK cascades. Compounds available from Tocris are listed.

Alzheimer's

Alzheimer's Poster

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Autophagy

Autophagy Poster

Autophagy is a cellular process used by cells for degradation and recycling. Written by Patricia Boya and Patrice Codogno, this poster summarizes the molecular machinery, physiology and pathology of autophagy. Compounds available from Tocris are listed.

Parkinson's

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Programmed Cell Death

Programmed Cell Death Poster

There are two currently recognized forms of programmed cell death: apoptosis and necroptosis. This poster summarizes the signaling pathways involved in apoptosis, necroptosis and cell survival following death receptor activation, and highlights the influence of the molecular switch, cFLIP, on cell fate.

Pathways for Ferroptosis

MAPK

MAPK Signaling Pathway

The mitogen-activated protein kinase pathway evokes an intracellular signaling cascade in response to extracellular stimuli such as heat and stress. It can influence cell division, metabolism and survival.