The chemical basis of ferroptosis

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Abstract

Lipid peroxidation underlies the mechanism of oxidative cell death now known as ferroptosis. This modality, distinct from other forms of cell death, has been intensely researched in recent years owing to its relevance in both degenerative disease and cancer. The demonstration that it can be modulated by small molecules in multiple pathophysiological contexts offers exciting opportunities for novel pharmacological interventions. Herein, we introduce the salient features of lipid peroxidation, how it can be modulated by small molecules and what principal aspects require urgent investigation by researchers in the field. The central role of non-enzymatic reactions in the execution of ferroptosis will be emphasized, as these processes have hitherto not been generally considered ‘druggable’. Moreover, we provide a critical perspective on the biochemical mechanisms that contribute to cell vulnerability to ferroptosis and discuss how they can be exploited in the design of novel therapeutics.

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Fig. 1: Lipid peroxidation occurs by a free-radical chain reaction (autoxidation) or enzymatic oxygenation.
Fig. 2: Key contributors to ferroptotic cell death.
Fig. 3: Inhibition of ferroptosis by radical-trapping antioxidants.
Fig. 4: Off-target RTA activity of lipoxygenase inhibitors.
Fig. 5: Key considerations for ferroptosis inhibition by radical-trapping antioxidants.
Fig. 6: Illustration of human diseases in which ferroptosis inhibitors/activators could modulate disease progression.

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Conrad, M., Pratt, D.A. The chemical basis of ferroptosis. Nat Chem Biol 15, 1137–1147 (2019) doi:10.1038/s41589-019-0408-1

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