Ferroptosis
Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides. Ferroptosis is biochemically, genetically, and morphologically distinct from other forms of regulated cell death such as apoptosis and necroptosis. Oxytosis/ferroptosis can be initiated by the failure of the glutathione-dependent antioxidant defenses, resulting in unchecked lipid peroxidation and eventual cell death. Lipophilic antioxidants and iron chelators can prevent ferroptotic cell death.
Researchers have identified roles in which oxytosis/ferroptosis can contribute to the medical field, such as the development of cancer therapies. Ferroptosis activation plays a regulatory role on growth of tumor cells in the human body. However, the positive effects of oxytosis/ferroptosis could be potentially neutralized by its disruption of metabolic pathways and disruption of homeostasis in the human body. Since oxytosis/ferroptosis is a form of regulated cell death, some of the molecules that regulate oxytosis/ferroptosis are involved in metabolic pathways that regulate cysteine exploitation, glutathione state, nicotinamide adenine dinucleotide phosphate function, lipid peroxidation, and iron homeostasis.
History
In 1989, work by the groups of Joseph T. Coyle and Ronald Schnaar showed in a neuronal cell line that excess exposure to glutamate or lowered cystine causes a decrease in glutathione levels, an accumulation in intracellular peroxides, and cytotoxicity. Later work by Pamela Maher and David Schubert noted the distinction of this cell death process from apoptosis, describing it as oxidative glutamate toxicity or oxytosis. In 2012, a study by Brent Stockwell and Scott Dixon characterized the iron dependence of this cell death process and coined the term ferroptosis. Oxytosis and ferroptosis are now thought to be the same cell death mechanism.Other early studies regarding the connection between iron and lipid peroxidation, cystine deprivation and oxidative cell death, the activity and importance of glutathione peroxidase 4, and the identification of small molecules that induce ferroptosis were key to the eventual characterization of ferroptosis.
Mechanism
The hallmark feature of oxytosis/ferroptosis is the iron-dependent accumulation of oxidatively damaged phospholipids, i.e., lipid peroxides. The implication of Fenton chemistry via iron is crucial for the generation of reactive oxygen species and this feature can be exploited by sequestering iron in lysosomes. Ferroptosis has been shown to involve distinct cellular organelles, which includes peroxisomes, mitochondria, the endoplasmic reticulum and lysosomes. It has been a debate in the scientific community, where ferroptosis is initiated in the cell, and now research points to the lysosome, where the chemical environment are favorable. Oxidation of phospholipids can occur when free radicals abstract electrons from a lipid molecule, thereby promoting their oxidation.The primary cellular mechanism of protection against oxytosis/ferroptosis is mediated by the selenoprotein GPX4, a glutathione-dependent hydroperoxidase that converts lipid peroxides into non-toxic lipid alcohols. Recently, a second parallel protective pathway was independently discovered by two labs that involves the oxidoreductase FSP1. FSP1 enzymatically reduces non-mitochondrial coenzyme Q10, thereby generating a potent lipophilic antioxidant that suppresses the propagation of lipid peroxides. Vitamin K is also reduced by FSP1 to a hydroquinone species that also acts as a radical-trapping antoxidant and suppressor of ferroptosis. A similar mechanism for a cofactor moonlighting as a diffusable antioxidant was discovered in the same year for tetrahydrobiopterin, a product of the rate-limiting enzyme GTP cyclohdrolase 1.
Replacing natural polyunsaturated fatty acids with deuterated PUFA, which have deuterium in place of the bis-allylic hydrogens, can prevent cell death induced by erastin or RSL3. These deuterated PUFAs effectively inhibit ferroptosis and various chronic degenerative diseases associated with ferroptosis.
Live-cell imaging has been used to observe the morphological changes that cells undergo during oxytosis/ferroptosis. Initially the cell contracts and then begins to swell. Perinuclear lipid assembly is observed immediately before oxytosis/ferroptosis occurs. After the process is complete, lipid droplets are redistributed throughout the cell.
Biology
Ferroptosis was initially characterized in human cell lines and has been since found to occur in other mammals, avians, worms, and plants. Ferroptosis has also been demonstrated in canine cancer cell models. There have been limited studies in other model organisms such as D. melanogaster. Elements related to components of the ferroptosis pathway have been identified in archaea, bacteria, and fungi, though it is unclear the extent to which ferroptosis occurs in these organisms. Further studies in this area may reveal an ancient origin for ferroptosis.Unlike other forms of cell death, ferroptosis has been shown to propagate between cells in a wave-like manner. This phenomenon is promoted by secretion of galectin-13 during ferroptosis. Mechanistically, galectin-13 binds to CD44, inhibiting CD44-mediated membrane localization of SLC7A11.
In development
During embryonic development, many cells die via apoptosis and other cell death pathways for various purposes including morphogenesis tissue sculpting, controlling cell numbers, and quality control. In 2024, it was found that ferroptosis plays a role in normal physiology during embryonic development and muscle remodelling, propagating in millimeter-length waves through the developing avian limb. The exact pro-ferroptotic signal that is transmitted between cells and the manner by which these ferroptotic waves are bounded remain to be characterized.Therapeutic relevance
Fundamental discoveries uncovering the biology of ferroptosis and translational studies showing the disease relevance of ferroptosis have motivated efforts to develop therapeutics that modulate ferroptosis. For example, Kojin Therapeutics and PTC Therapeutics are exploring ferroptosis modulation for treatment of cancer and Friedrich's ataxia. Ferroptosis has been implicated in a range of different diseases including cancer, ischemia/reperfusion injury, inflammation, neurodegeneration, and kidney injury.Cancer
Ferroptosis has been explored as a strategy to selectively kill cancer cells.Oxytosis/ferroptosis has been implicated in several types of cancer, including:
- Breast
- Acute myeloid leukemia
- Pancreatic ductal adenocarcinoma
- Ovarian
- B-cell lymphoma
- Renal cell carcinomas
- Lung
- Glioblastoma
In various contexts, resistance to cancer therapy is associated with a mesenchymal state. A pair of studies in 2017 found that these cancer cells in this therapy-induced drug-resistant state exhibit a greater dependence on GPX4 to suppress ferroptosis. Consequently, GPX4 inhibition represents a possible therapeutic strategy to mitigate acquired drug resistance.
Neurodegeneration
Neural connections are constantly changing within the nervous system. Synaptic connections that are used more often are kept intact and promoted, while synaptic connections that are rarely used are subject to degradation. Elevated levels of synaptic connection loss and degradation of neurons are linked to neurodegenerative diseases. More recently, oxytosis/ferroptosis has been linked to diverse brain diseases, in particular, Alzheimer's disease, amyotrophic lateral sclerosis, and Parkinson's disease. Two new studies show that oxytosis/ferroptosis contributes to neuronal death after intracerebral hemorrhage. Neurons that are degraded through oxytosis/ferroptosis release lipid metabolites from inside the cell body. The lipid metabolites are harmful to surrounding neurons, causing inflammation in the brain. Inflammation is a pathological feature of Alzheimer's disease and intracerebral hemorrhage.Recent studies have suggested that oxytosis/ferroptosis contributes to neuronal cell death after traumatic brain injury. Hypoxic brain injury in resuscitated patients shows retrospective evidence of ferroptosis. Additionally there is evidence that the prion protein and pathogenic prions PrPSc contribute to ferroptosis sensitivity in the brain, a condition that is enhanced by RAC3 expression.
Acute kidney injury
Ferroptosis occurs during acute kidney injury in various cellular and animal models. Deficiencies in ferroptosis suppressor enzymes such as GPX4 and FSP1 sensitize kidneys to tubular ferroptosis during kidney IRI, thus inhibition of ferroptosis may be of therapeutic benefit. However, in premenopausal women this therapeutic potential might be limited due to intrinsic anti-ferroptotic effects of estrogen.During chemotherapy treatment, ferroptosis contributes to acute kidney injury. Reagents to image ferroptosis have been developed to monitor anticancer drug-induced acute kidney injury in mouse models.