FINO2 Initiates Ferroptosis Through GPX4 Inactivation and Iron Oxidation

By M. Gaschler, A. Andia, Hengrui Liu, J. Csuka, Brisa Hurlocker, Christopher A. Vaiana, Daniel W. Heindel, Dylan S Zuckerman, P. H. Bos, Eduard Reznik and 14 more. Nature Chemical Biology, 2018

661 citations recorded by the source corpus.

AbstractFerroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2 is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and structural features necessary for ferroptosis initiation by FINO2. We found that FINO2 requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO2 does not inhibit system xc– or directly target the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of ferroptosis.FINO2 is a small molecule that requires the endoperoxide moiety and hydroxyl group to promote ferroptosis through indirect inhibition of GPX4 enzymatic function and direct oxidation of iron, resulting in increased lipid peroxidation.

Subfields: Cancer Research, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/839daa18fc804f84e8751b5e07c8f70f0a63c14f

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In Cancer Research

1. Tal Hirschhorn
2. Qing-zhang Tuo
3. P. Lei
4. Brent R. Stockwell

In Oncology

1. Tal Hirschhorn
2. Brent R. Stockwell
3. Scott J. Dixon
4. R. Kang
5. D. Tang

In Pulmonary and Respiratory Medicine

1. Tal Hirschhorn
2. Qing-zhang Tuo
3. P. Lei
4. Brent R. Stockwell
5. Scott J. Dixon
6. D. Tang
7. R. Kang
8. M. Conrad

Citations in the corpus

• Ferroptosis: mechanisms and links with diseases (2021, background): “FINO2, an endoperoxide-containing 1,2-dioxolane, can oxidize Fe leading to lipid peroxidation and kill BJeLR cancer cells via ferroptosis.(170) Silencing the expression of prominin2 decreases the cellular iron export of RSL3-treated mammary epithelial (MCF10A cells) and breast carcinoma cells (Hs578”