Ferroptosis

Ferroptosis is a form of regulated cell death, distinct from apoptosis and necroptosis, defined by the iron-dependent accumulation of lipid peroxides in cellular membranes to lethal levels. Its central axis is the cystine/glutamate antiporter system xc− (SLC7A11/SLC3A2), which supplies the cysteine required for glutathione (GSH) synthesis, and glutathione peroxidase 4 (Gpx4), the GSH-dependent enzyme that reduces phospholipid hydroperoxides to unreactive alcohols. Deplete GSH or inactivate Gpx4 and peroxidized lipids go unreduced, whereupon labile ferrous iron propagates the peroxidation chain reaction through Fenton chemistry. A second, GSH-independent defense runs in parallel at the membrane: ferroptosis suppressor protein 1 (FSP1) regenerates reduced coenzyme Q10 as a radical-trapping antioxidant, which is why Gpx4 inhibition alone does not kill every cell. Susceptibility is set further upstream by membrane composition, since acyl-CoA synthetase long-chain family member 4 (ACSL4) activates polyunsaturated fatty acids to acyl-CoAs that downstream acyltransferases esterify into phospholipids, and membranes rich in these species are the easiest to peroxidize. Iron-handling proteins such as ferritin light chain (FTL) govern the labile iron pool that drives the reaction, while the transcription factor Nrf2, through targets including heme oxygenase 1 and SLC7A11, is the principal stress-responsive brake on the whole process, with reactive oxygen species and general oxidative stress serving as both its drivers and its readouts.

Because ferroptosis sits at the intersection of iron homeostasis, redox balance, and lipid metabolism, it has been implicated across oncology and neurology, and the therapeutic logic runs in opposite directions in the two. Many tumors evade ferroptosis by upregulating ferroptosis-suppressive programs, which makes forced induction attractive: sensitivity to Gpx4 or system xc− disruption has been explored in triple-negative breast cancer, hepatocellular carcinoma, non-small cell lung cancer, and pulmonary sarcomatoid carcinoma, and ferroptosis-related gene signatures are being evaluated as prognostic and drug-sensitivity biomarkers alongside other regulated cell death modes such as cuproptosis. The pathway also shapes tumor immunity: CD8+ T cell–derived interferon gamma suppresses SLC7A11 and sensitizes tumor cells, linking ferroptosis to checkpoint inhibitor and anti-Programmed cell death 1 (PD-1) response, while tumor-intrinsic suppression of it has been associated with immunotherapy resistance.

In the nervous system the same features that make ferroptosis useful against cancer make it pathogenic. Iron accumulation, lipid peroxidation, and oxidative stress accompany the amyloid beta and tau pathology of Alzheimer's disease and the α-synuclein–associated loss of dopaminergic neurons in Parkinson's disease, motivating ferroptosis inhibitors, iron chelation, and antioxidant nanotherapeutics as neuroprotective approaches. Comparable roles have been proposed in chronic kidney disease, metabolic dysfunction–associated steatotic liver disease, and epithelial injury in chronic obstructive pulmonary disease. In all of these the therapeutic goal is suppression rather than induction, which is the practical reason ferroptosis is pursued as a target from both directions at once.