Figure 2. Old and new representations of ferroptosis.

(A) Several key elements of the ferroptosis mechanism, depicted using a traditional pathway map. This pathway map encompasses far less than is known about ferroptosis. Some key inputs are also not easily captured in this map due to conflicting evidence in the literature. This map also contains substantial redundancy, which makes it difficult to intuit how inhibition or activation of any one element modulates ferroptosis. Key small molecule inducers of ferroptosis are indicated in red. NOX: NAD(P)H oxidase, LOX: lipoxygenase, CI/CIII: complex I and complex III of the mitochondrial electron transport chain. POR: NAD(P)H-cytochrome P450 reductase. Notional peroxidized phospholipid acyl chains are denoted in red; purple indicates termination of the phospholipid peroxidation process.

(B) A new depiction of ferroptosis as a flexible mechanism involving a constellation of related biochemical mechanisms. The core mechanism of lipid peroxidation (magenta) involves iron, and different configurations of oxidizable lipids and lipid peroxidation initiating reactions and enzymes. The core lipid peroxidation mechanism is surrounded by several biochemically distinct inner defense mechanisms (blue). The core mechanism and the inner defenses are in turn modulated by a regulatory penumbra that may encompass dozens or hundreds of regulatory inputs, only some of which are depicted here (green).

(C) Mechanistic details of the core lipid peroxidation mechanism, illustrating the processes of (auto)initiation, propagation, and termination of the chain reaction. Key points of intervention by radical trapping antioxidants (RTAs), peroxidase mimics, and iron chelators, are indicated.