- Ferroptosis is a regulated form of cell death characterised by iron‑dependent lipid peroxidation and catastrophic membrane damage. Unlike apoptosis, necroptosis or pyroptosis, ferroptosis is defined by metabolic dysfunction rather than caspase activation or pore formation. It arises when antioxidant defences fail to prevent the accumulation of toxic lipid hydroperoxides, leading to oxidative destruction of cellular membranes. Ferroptosis plays essential roles in neurodegeneration, cancer biology, immunity and metabolic disease, making it a major focus of modern cell‑death research.
- The central driver of ferroptosis is iron‑dependent oxidative stress. Free intracellular iron catalyses the Fenton reaction, generating reactive oxygen species (ROS) that attack polyunsaturated fatty acids (PUFAs) within phospholipids. These oxidised lipids destabilise membranes, disrupt ion homeostasis and ultimately cause cell rupture. Because iron availability directly influences ferroptosis sensitivity, iron‑handling proteins such as transferrin, ferritin and ferroportin are key regulators of this pathway.
- Cells normally prevent ferroptosis through robust antioxidant systems. The most important is the glutathione (GSH)–GPX4 axis. Glutathione peroxidase 4 (GPX4) reduces lipid hydroperoxides to non‑toxic alcohols, protecting membranes from oxidative damage. GPX4 requires glutathione, which is synthesised from cysteine imported via the cystine/glutamate antiporter system Xc⁻. When cystine uptake is inhibited, glutathione levels fall, GPX4 activity collapses and lipid peroxides accumulate, triggering ferroptosis.
- Ferroptosis is also shaped by lipid metabolism. Enzymes such as ACSL4 and LPCAT3 incorporate PUFAs into membrane phospholipids, increasing susceptibility to peroxidation. Conversely, monounsaturated fatty acids (MUFAs) and lipid‑repair enzymes such as FSP1 and DHODH provide protection. Mitochondria further influence ferroptosis through ROS production, metabolic flux and iron–sulphur cluster turnover, linking ferroptosis to broader cellular stress pathways including the oxidative stress response and proteostasis network.
- Ferroptosis interacts with other regulated cell‑death pathways. Severe ER stress can sensitise cells to ferroptosis by disrupting redox balance and lipid homeostasis. Autophagy contributes through ferritinophagy, a selective process that degrades ferritin and increases free iron, thereby amplifying lipid peroxidation. Crosstalk with apoptosis and necroptosis ensures that cells use the most appropriate death pathway depending on the nature of the stress.
- Ferroptosis plays important physiological and pathological roles. In neurodegenerative diseases such as Alzheimer’s, Parkinson’s and ALS, iron accumulation and oxidative stress promote ferroptotic neuronal loss. In cancer, ferroptosis can suppress tumour growth, and many tumours exhibit altered lipid metabolism or GPX4 dependency, making ferroptosis induction a promising therapeutic strategy. Ferroptosis also contributes to ischemia–reperfusion injury, organ damage, infection responses and inflammatory disease.
- In summary, ferroptosis is an iron‑dependent form of regulated cell death driven by lipid peroxidation and failure of antioxidant defences. Through interactions with metabolism, redox biology, autophagy and cellular stress pathways, ferroptosis shapes tissue homeostasis and disease progression. Its unique biochemical signature and therapeutic potential make ferroptosis one of the most intensively studied cell‑death mechanisms today.
