Ferroptotic pores induce Ca2+ fluxes and ESCRT-III activation to modulate cell death kinetics.

Ferroptosis is an iron-dependent form of regulated necrosis associated with lipid peroxidation. Despite its key role in the inflammatory outcome of ferroptosis, little is known about the molecular events leading to the disruption of the plasma membrane during this type of cell death. Here we show that a sustained increase in cytosolic Ca2+ is a hallmark of ferroptosis that precedes complete bursting of the cell. We report that plasma membrane damage leading to ferroptosis is associated with membrane nanopores of a few nanometers in radius and that ferroptosis, but not lipid peroxidation, can be delayed by osmoprotectants. Importantly, Ca2+ fluxes during ferroptosis induce the activation of the ESCRT-III-dependent membrane repair machinery, which counterbalances the kinetics of cell death and modulates the immunological signature of ferroptosis. Our findings with ferroptosis provide a unifying concept that sustained increase of cytosolic Ca2+ prior to plasma membrane rupture is a common feature of regulated types of necrosis and position ESCRT-III activation as a general protective mechanism in these lytic cell death pathways.

Ferroptosis in Cancer Cell Biology.

A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Importantly, tumour cells escaping other forms of cell death have been suggested to maintain or acquire sensitivity to ferroptosis. Therefore, therapeutic exploitation of ferroptosis in cancer has received increasing attention. Here, we systematically review current literature on ferroptosis signalling, cross-signalling to cellular metabolism in cancer and a potential role for ferroptosis in tumour suppression and tumour immunology. By summarising current findings on cell biology relevant to ferroptosis in cancer, we aim to point out new conceptual avenues for utilising ferroptosis in systemic treatment approaches for cancer.