Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Aug;23(8):4900-4912.
doi: 10.1111/jcmm.14511. Epub 2019 Jun 24.

Molecular Mechanisms of Ferroptosis and Its Role in Cancer Therapy

Affiliations
Free PMC article
Review

Molecular Mechanisms of Ferroptosis and Its Role in Cancer Therapy

Tao Xu et al. J Cell Mol Med. .
Free PMC article

Abstract

Ferroptosis is a newly defined programmed cell death process with the hallmark of the accumulation of iron-dependent lipid peroxides. The term was first coined in 2012 by the Stockwell Lab, who described a unique type of cell death induced by the small molecules erastin or RSL3. Ferroptosis is distinct from other already established programmed cell death and has unique morphological and bioenergetic features. The physiological role of ferroptosis during development has not been well characterized. However, ferroptosis shows great potentials during the cancer therapy. Great progress has been made in exploring the mechanisms of ferroptosis. In this review, we focus on the molecular mechanisms of ferroptosis, the small molecules functioning in ferroptosis initiation and ferroptosis sensitivity in different cancers. We are also concerned with the new arising questions in this particular research area that remains unanswered.

Keywords: cancer therapy; drug resistance; ferroptosis; programmed cell death; small molecules.

Conflict of interest statement

The authors confirm that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Mechanisms of ferroptosis induction. Inhibition of system x c deprives cellular cysteine, leading to GSH deletion and GPX4 inactivation. GSH can be synthesized from methionine through the transsulphuration pathway which is inhibited by cysteinyl‐tRNA synthetase. RSL3 inhibits the activity of GPX4 by covalent binding with GPX4. GPX4 inactivation leads to the accumulation of lipid peroxides and final ferroptosis. Enzymes (GLS2 and GOT1) involved in glutaminolysis regulate ferroptosis process. The tricarboxylic acid (TCA) cycle promotes cellular GSH deletion and leads to ferroptosis in combination with cysteine deprivation. The mitochondrial genes (ACSF2, CS) are all involved in ferroptosis regulation. ER stress induced by ferroptotic reagents promotes ferroptosis through ATF4‐dependent CHAC 1 expression. Lysosome is also involved in ferroptosis induction through autophagy process or cathepsin B release. Lysosome ROS contributes to the lipid ROS production
Figure 2
Figure 2
Iron metabolism and lipid peroxides accumulation. Transferrin transports the iron into cells by the TFR1‐mediated endocytosis. Ferroportin exports and decreases the cellular iron. Cellular iron is involved in the normal life process such as DNA synthesis, metastasis, cell cycle progression, angiogenesis or mitochondrial iron metabolism. Ferritin is the iron storage protein in the cells. Only the free iron is involved in the Fenton reaction. Fe2+ promotes the lipid peroxides accumulation through Fenton reaction and lipid oxidation. IRP1/2 regulates the iron metabolism genes by binding with the 3‐′ or 5‐′ UTR of the mRNAs
Figure 3
Figure 3
Potential application of ferroptosis in overcoming cancer cells' drug resistance. EMT process promotes the mesenchymal state of cancer cells through the activation of ZEB1. The surviving cells (persister cells) after several rounds of chemotherapy obtained the mesenchymal features. Nrf2 target genes are down‐regulated, and the levels of NADPH and GSH are decreased in these cells with mesenchymal state. GPX4 inactivation is lethal to cancer cells with mesenchymal state

Similar articles

See all similar articles

Cited by 4 articles

References

    1. Dixon S, Lemberg K, Lamprecht M, et al. Ferroptosis: an iron‐dependent form of nonapoptotic cell death. Cell. 2012;149(5):1060‐1072. - PMC - PubMed
    1. Conrad M, Sato H. The oxidative stress‐inducible cystine/glutamate antiporter, system x (c) (‐): cystine supplier and beyond. Amino Acids. 2012;42(1):231‐246. - PubMed
    1. Martin HL, Teismann P. Glutathione–a review on its role and significance in Parkinson's disease. FASEB J. 2009;23(10):3263‐3272. - PubMed
    1. Ishii T, Bannai S, Sugita Y. Mechanism of growth stimulation of L1210 cells by 2‐mercaptoethanol in vitro. Role of the mixed disulfide of 2‐mercaptoethanol and cysteine. J Biol Chem. 1981;256(23):12387‐12392. - PubMed
    1. Dixon SJ, Patel DN, Welsch M, et al. Pharmacological inhibition of cystine‐glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. 2014;3:e02523. - PMC - PubMed

Publication types

Feedback