Global Survey of Cell Death Mechanisms Reveals Metabolic Regulation of Ferroptosis

By K. Shimada, R. Skouta, A. Kaplan, W. Yang, M. Hayano, Scott J. Dixon, L. Brown, Carlos A. Valenzuela, Adam J. Wolpaw, Brent R. Stockwell. Nature Chemical Biology, 2016

934 citations recorded by the source corpus.

Apoptosis is known as programmed cell death. Some non-apoptotic cell death is increasingly recognized as genetically controlled, or ‘regulated’. However, the full extent and diversity of these alternative cell death mechanisms remains uncharted. Here, we surveyed the landscape of pharmacologically-accessible cell death mechanisms. Of 56 caspase-independent lethal compounds, modulatory profiling revealed ten inducing three types of regulated non-apoptotic cell death. Lead optimization of one of the ten resulted in the discovery of FIN56, a specific inducer of ferroptosis. Ferroptosis occurs when the lipid repair enzyme GPX4 is inhibited. We found that FIN56 promotes degradation of GPX4. We performed chemoproteomics to reveal that FIN56 also binds to and activates squalene synthase, an enzyme involved in the cholesterol synthesis, in a manner independent of GPX4 degradation. These discoveries reveal that dysregulation of lipid metabolism is associated with ferroptosis. This systematic approach is a means to discover and characterize novel cell death phenotypes.

Subfields: Cancer Research, Oncology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/08b9f280c6b6698a57cfa89ce501792a4765c7e9

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Brent R. Stockwell
2. Guido Kroemer
3. D. Tang
4. R. Kang
5. Ralph J. Deberardinis
6. M. V. Vander Heiden
7. Navdeep S. Chandel
8. M. Conrad

In Oncology

1. Guido Kroemer
2. D. Tang
3. R. Kang
4. L. Galluzzi
5. Brent R. Stockwell
6. Scott J. Dixon
7. M. Conrad
8. Moshe Oren

In Pulmonary and Respiratory Medicine

1. Brent R. Stockwell
2. D. Tang
3. R. Kang
4. Guido Kroemer
5. Tal Hirschhorn
6. M. Conrad
7. Scott J. Dixon
8. F. Ursini

Citations in the corpus

• The cell biology of ferroptosis (2024, neutral): “Regardless, ferroptosis is defined as a regulated form of cell death because it is possible to modulate (that is, enhance or suppress) sensitivity by changing the function of specific proteins and pathways in the cell 90,202 .”
• Ferroptosis in cancer: from molecular mechanisms to therapeutic strategies (2024, background): “45 In 2017, ACSL4 was further identi fi ed as an essential component for ferroptosis execution by promoting arachidonic acid (AA) or adrenic acid (AdA) esteri fi cation into phosphatidy-lethanolamines (PEs).”
• Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “Some of the molecular circuitries regulating the initial steps of ferroptosis have been recently unveiled by employing (1) specific ferroptosis-inducing agents, including erastin [543, 544], RSL3 [543, 544], and FIN56 [545]; and (2) specific ferroptosis-inhibiting agents, including ferrostatins [539”
• Ferroptosis as a target for protection against cardiomyopathy (2019, result): “However, consistent with previous results (3, 24), we found that DOX-induced cell death could not be rescued in vitro using either iron/metal chelators or Fer-1 (SI Appendix, Fig.”
• Emerging mechanisms and disease relevance of ferroptosis (2020, background): “For example, statins, which inhibit mevalonate-derived CoQ10 by blocking the enzyme HMG CoA reductase, also sensitize cells to ferroptosis [30].”