Ferroptosis

Ferroptosis is an iron-dependent form of regulated cell death driven by the uncontrolled peroxidation of polyunsaturated-fatty-acid-containing phospholipids in cell membranes. Unlike apoptosis, necroptosis, or pyroptosis, ferroptosis has no canonical upstream “activation signal”: it is instead continuously suppressed by dedicated antioxidant surveillance systems — most notably the system xc−-glutathione-GPX4 axis — and occurs only once these safeguards are overwhelmed or pharmacologically disrupted, allowing iron to convert lipid hydroperoxides into radicals that propagate membrane damage until rupture. Ferroptosis sensitivity is further shaped by how much free (“labile”) iron is available inside the cell: iron sequestered safely in ferritin is comparatively inert, while iron released by ferritinophagy (autophagic ferritin degradation) can fuel the reaction, so cells can also modulate ferroptosis susceptibility by controlling ferritin’s availability — for example, by transiently sequestering ferritin inside stress granules. Because many apoptosis-resistant and therapy-resistant cancer cells become selectively dependent on these antioxidant and iron-handling systems, ferroptosis induction is being explored as a strategy to kill malignancies that have evaded other death pathways.