On the lethal mechanism of class III ferroptosis inducers

Abstract

Ferroptosis is an oxidative form of non-apoptotic cell death that is important for human biology. This process can be induced in cultured cells by at least four structurally and mechanistically distinct classes of ferroptosis inducing (FIN) small molecules. These four classes of FINs are distinguished based on molecular target and mechanism of action. The lethal mechanism of the prototypic oxime-containing class III FIN, FIN56, is unique and poorly understood. FIN56 is proposed to cause ferroptosis by depleting coenzyme Q10 and degrading glutathione peroxidase 4 (GPX4). Curiously, the FIN56 analogs caspase independent lethal 56 (CIL56) and tegavivint also trigger non-apoptotic cell death but not ferroptosis. Tegavivint is a drug candidate currently being tested in humans for the treatment of cancer. Here, we review our understanding of the FIN56 lethal mechanism with a view to guiding future investigations into a privileged chemical scaffold that possesses unusual lethal activity in cancer cells.

Keywords

Lipid peroxidation / necrosis / erastin / RSL3 / FIN56 / CIL56 / tegavivint

Acknowledgements

We thank M. Murray, P. Sutton, A. Gautam, S. Manukian, N. Haseley, I. Srivastava, and J. Goncalves for comments on this work. Figures were created with ChemDraw and Adobe Illustrator.

Authors contribution

Joseph A, Dixon SJ: Conceptualization, writing-original draft, writing-review & editing.

Conflicts of interest

Scott J. Dixon holds patents related to ferroptosis and is an Editorial Board Member of Ferroptosis and Oxidative Stress. The other author declares no conflict of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by the NIH (Grant No. GM122923 to S.J.D.).

Copyright

© The Author(s) 2026.

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