Ferroptosis is a regulated form of cell death characterized by iron dependent lipid peroxidation. Unlike apoptosis or necrosis, it is defined by oxidative damage to polyunsaturated fatty acids in cell membranes, driven by reactive oxygen species and catalytic iron.

A central protective system against ferroptosis is the glutathione peroxidase 4, or GPX4, pathway. GPX4 uses glutathione to detoxify lipid peroxides. When cystine import via system Xc minus is blocked, glutathione synthesis falls, GPX4 activity declines and lipid peroxides accumulate, triggering ferroptosis. Inhibitors of system Xc minus or GPX4 are common experimental tools to induce this process.

The metabolic context of the cell strongly influences ferroptosis sensitivity. Polyunsaturated fatty acid containing phospholipids are the key substrates for peroxidation. Enzymes that incorporate these fatty acids into membranes promote susceptibility, while pathways that enrich membranes with monounsaturated fatty acids are protective. Mitochondrial metabolism, NADPH availability and coenzyme Q also modulate oxidative stress and ferroptosis.

Iron handling is crucial. Labile iron participates in Fenton chemistry to generate radicals that attack lipids. Transport, storage and export proteins that change intracellular iron pools can enhance or limit ferroptosis.

Ferroptosis has important implications in disease. It can suppress tumors by killing cancer cells that are highly dependent on iron and lipid metabolism, but it may also contribute to neurodegeneration, ischemia reperfusion injury and organ damage. Current research focuses on small molecules that either induce ferroptosis in resistant cancers or inhibit it to protect vulnerable tissues, as well as on identifying biomarkers that distinguish ferroptosis from other death pathways.