Mechanisms underlying propagation of ferroptotic cell death.

Necrotic zones in tissues occur in a wide variety of diseases. Ferroptosis, an iron-promoted necrosis driven by lipid peroxidation, has been identified as a key cell death modality in these conditions. Cells undergoing ferroptosis are unique in that they can induce death in their neighbours. Here we review salient aspects of ferroptosis propagation on the molecular, cellular and tissue levels. Cell death propagation is restricted by several ferroptosis-suppression systems. Glutathione peroxidase 4 (GPX4) and ferroptosis-suppressor protein 1 (FSP1) are now well established as master regulators, but various additional systems dictate ferroptosis sensitivity. We discuss how these mechanisms contribute to the suppression of cell death propagation, and how they cause various tissues to be more or less resistant to ferroptosis propagation. Understanding tissue-specific dynamics is critical to interpret the beneficial effects and limitations of future therapeutic approaches for ferroptosis-driven diseases.