Ferroptosis
Ferroptosis is an iron-dependent form of regulated cell death that is morphologically, biochemically, and genetically distinct from apoptosis, necroptosis, and autophagy, primarily driven by the lethal accumulation of phospholipid hydroperoxides in cellular membranes.[1] First identified in 2003 through synthetic lethal screening of small molecules targeting oncogenic RAS-mutant cancer cells and formally named in 2012, ferroptosis was characterized as a non-apoptotic process triggered by compounds like erastin, which inhibits the cystine/glutamate antiporter system xc⁻, leading to glutathione depletion and subsequent oxidative damage.[1] At its core, the mechanism involves iron-catalyzed lipid peroxidation of polyunsaturated fatty acids (PUFAs) via Fenton-like reactions, generating toxic reactive oxygen species (ROS) that overwhelm antioxidant defenses, particularly the glutathione peroxidase 4 (GPX4)-dependent reduction of lipid hydroperoxides; this results in plasma membrane rupture without caspase activation or typical apoptotic features like chromatin condensation.[2] Ferroptosis is regulated by a complex network of metabolic pathways, including iron homeostasis (e.g., via ferritinophagy), lipid metabolism (e.g., PUFA incorporation into phospholipids by ACSL4), and amino acid transport, with key inducers like RSL3 directly inhibiting GPX4 and inhibitors such as ferrostatin-1 scavenging lipid ROS.[3] Physiologically, ferroptosis contributes to embryonic development, T-cell differentiation, and macrophage-mediated antiviral responses, while pathologically, it is implicated in ischemia-reperfusion injuries, acute kidney failure, and neurodegeneration.[4] In oncology, ferroptosis represents a promising therapeutic target, as many cancers exhibit vulnerability to its induction—exploiting metabolic weaknesses like high iron levels and lipid peroxidation sensitivity—potentially synergizing with immunotherapies and chemotherapy, whereas its inhibition may mitigate ferroptosis-driven tissue damage in non-malignant diseases.[5]Definition and Characteristics
Core Features
Ferroptosis is defined as a form of regulated cell death that is distinct from apoptosis, necrosis, and autophagy, characterized by the iron-dependent accumulation of lipid peroxides that ultimately leads to oxidative damage and rupture of the plasma membrane.[6] This process is triggered by small-molecule inducers such as erastin, which inhibits cystine uptake via the system xc- transporter, thereby depleting glutathione and impairing antioxidant defenses.[7] Morphologically, ferroptotic cells exhibit shrunken mitochondria with condensed membranes, diminished or absent cristae, and increased mitochondrial membrane density, while the overall cell and nuclear morphology remains relatively intact without the formation of apoptotic bodies or autophagosomes. These ultrastructural changes, observable via electron microscopy, distinguish ferroptosis from other cell death modalities and reflect the profound impact of lipid peroxidation on organelle integrity. Biochemically, ferroptosis is marked by the excessive accumulation of lipid hydroperoxides, particularly those derived from polyunsaturated fatty acids (PUFAs) such as arachidonic acid, coupled with elevated levels of reactive oxygen species (ROS) originating from lipid oxidation rather than general oxidative stress.[8] This peroxidation chain reaction is catalyzed by labile iron pools through the Fenton reaction, leading to the depletion of PUFA-containing phospholipids and membrane fragility.[8] Genetically, ferroptosis is identified by cellular sensitivity to inducers like erastin or RSL3 (a direct inhibitor of glutathione peroxidase 4, GPX4), alongside resistance to pharmacological inhibitors of apoptosis (e.g., caspase inhibitors like Z-VAD-fmk) and necroptosis (e.g., necrostatin-1).[6] These markers enable experimental distinction and highlight ferroptosis as a unique pathway amenable to targeted modulation. As of 2025, research has increasingly integrated ferroptosis with broader metabolic reprogramming, revealing overlaps with emerging cell death forms such as cuproptosis—driven by copper overload targeting tricarboxylic acid cycle proteins—and disulfidptosis—induced by disulfide stress in actin cytoskeleton proteins—through shared regulators like SLC7A11 and altered redox homeostasis.[9][10] These connections underscore ferroptosis's role in metabolic vulnerabilities, particularly in cancer and degenerative diseases, without altering its core iron-lipid axis.[9]Comparison to Other Cell Death Forms
Ferroptosis is distinguished from other regulated cell death pathways by its iron-dependent lipid peroxidation mechanism, which is caspase-independent and does not involve the inflammatory DNA release characteristic of necroptosis.[6] Unlike apoptosis, which relies on caspase activation and cytochrome c release for orderly dismantling of the cell, ferroptosis proceeds without nuclear fragmentation or apoptotic body formation, instead featuring progressive membrane damage from reactive oxygen species (ROS) accumulation in lipids.[11] In contrast to autophagy, which primarily involves protein degradation via autophagosomes and does not inherently lead to cell lysis unless excessive, ferroptosis centers on oxidative destruction of polyunsaturated fatty acids in cell membranes rather than cytoplasmic recycling.[12] While overlaps exist, such as shared ROS involvement with necroptosis or regulatory crosstalk with autophagy through ferritinophagy, ferroptosis maintains a unique identity defined by its iron-lipid axis.[11] Evolutionarily, ferroptosis is considered one of the most ancient forms of cell death, conserved across species and predating more specialized pathways like apoptosis, potentially serving as a primitive defense against oxidative stress in early life forms.[13] Initially suppressing inflammation due to the absence of classical inflammasome activation, ferroptosis can nevertheless trigger immunogenic cell death by releasing damage-associated molecular patterns (DAMPs), such as oxidized lipids, which alert the immune system in a manner distinct from the pro-inflammatory cytokine bursts in pyroptosis.[14] The following table summarizes key morphological, biochemical, and pharmacological distinctions among ferroptosis and selected cell death forms:| Aspect | Ferroptosis | Apoptosis | Necroptosis | Autophagy |
|---|---|---|---|---|
| Morphological | Mitochondrial shrinkage, fractured outer mitochondrial membranes, diminished cristae, normal nuclear morphology, eventual plasma membrane rupture | Cell shrinkage, chromatin condensation, nuclear fragmentation, apoptotic body formation | Cell swelling, organelle swelling, plasma membrane rupture | Cytoplasmic vacuolization, autophagosome formation, no immediate lysis |
| Biochemical | Iron-dependent lipid peroxidation, GPX4 depletion, ROS accumulation in lipids, caspase-independent | Caspase activation (e.g., caspase-3/7/9), cytochrome c release, DNA laddering | RIPK1/RIPK3/MLKL phosphorylation, membrane permeabilization, DAMP release | LC3 lipidation, mTOR inhibition, lysosomal degradation of proteins/organelles |
| Pharmacological | Induced by erastin/RSL3; inhibited by ferrostatin-1, liproxstatin-1, iron chelators | Induced by staurosporine/TNF-α; inhibited by Z-VAD-fmk, BH3 mimetics (e.g., venetoclax as inducers, but inhibitors include Bcl-2 overexpression) | Induced by TNF-α (with caspase inhibition); inhibited by necrostatin-1 | Induced by rapamycin; inhibited by chloroquine, 3-MA |