Pathology

Neuroscience

Oxidative stress

Disease

Biology

Gene

Druggability

Epistemology

Philosophy

Apoptosis

Lipid peroxidation

Programmed cell death

Computer science

Computational biology

Mechanism (biology)

Cell biology

Computer security

Biochemistry

Medicine

Vulnerability (computing)

Nature Chemical Biology

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. This Perspective focuses on the chemical basis of ferroptotic cell death, discussing the prominent role of spontaneous chemical reactions, how they depend on enzyme-catalyzed processes and how to exploit this interplay for therapeutic benefit.

The chemical basis of ferroptosis