Targeting Ferroptosis: New Hope for As-Yet-Incurable Diseases

Ferroptosis is a pervasive, disease-relevant metabolic cell death pathway, entirely distinct from other known forms of regulated cell death. Ferroptosis is the root cause of a number of degenerative diseases and emerges as a liability for difficult-to-treat tumors. Ferroptosis modulation may unleash unprecedented opportunities for pharmacological intervention. Attaining control over life and death decisions facilitates the identification of new therapeutic strategies for diseases affected by early cell loss or resistance to cell death. In this context, ferroptosis, a prevailing form of non-apoptotic cell death marked by the iron-dependent oxidative destruction of lipid bilayers and metabolic aberrations, has attracted overwhelming interest among basic researchers and clinicians due to its relevance for a number of degenerative diseases, such as neurodegeneration, ischemia/reperfusion injury (IRI), and organ failure, as well as therapy-resistant tumors. As the ferroptotic death pathway offers various druggable nodes, it is anticipated that the preclinical and clinical development of ferroptosis modulators will unleash unprecedented opportunities for the treatment of as-yet-incurable diseases. Attaining control over life and death decisions facilitates the identification of new therapeutic strategies for diseases affected by early cell loss or resistance to cell death. In this context, ferroptosis, a prevailing form of non-apoptotic cell death marked by the iron-dependent oxidative destruction of lipid bilayers and metabolic aberrations, has attracted overwhelming interest among basic researchers and clinicians due to its relevance for a number of degenerative diseases, such as neurodegeneration, ischemia/reperfusion injury (IRI), and organ failure, as well as therapy-resistant tumors. As the ferroptotic death pathway offers various druggable nodes, it is anticipated that the preclinical and clinical development of ferroptosis modulators will unleash unprecedented opportunities for the treatment of as-yet-incurable diseases. one of five closely related fatty acid ligases that preferably activates long PUFAs by ligating them with coenzyme A. a reactive group on small molecules that can covalently inactivate the active-site selenocysteine of selenoproteins. describes a chemical reaction between ferrous iron (Fe2+) and hydrogen peroxide leading to the formation of the highly toxic hydroxyl radical (OH.), which can initiate lipid peroxidation and ferroptosis. the second mainstay in ferroptosis control, which acts independently of the GSH/GPX4 axis by regenerating CoQ10. a tripeptide comprising glutamate, cysteine, and glycine representing the most abundant intracellular electron donor for GSH-dependent enzymes in mammals (up to 10 mM). one of eight GPXs in mammals with unique enzyme activity to efficiently reduce lipid peroxides in cellular membranes thereby preventing lipid peroxidation. a disease condition whereby the oxygen supply to parts of an organ is transiently disrupted by occlusion of the vessel by a blood clot or during surgery. Restoration of the blood flow (i.e., reperfusion) may cause oxidative stress, massive cell death, and tissue injury. oxidative degradation of lipids, whereby free radicals 'steal' electrons from the lipids (i.e., PUFAs) in cellular membranes. This causes the formation of lipid radicals, which can spark the lipid peroxidation chain reaction. If not counteracted by antioxidant enzymes or RTAs, membranes are oxidatively destroyed leading to the rupturing of cells and ferroptosis. the first described form of regulated necrosis uncovered by the recognition that tumor necrosis factor alpha (TNFα) induces not only apoptosis and inflammation, but also necroptosis under specific cell contexts. unregulated forms of cell death mostly induced by physical impacts and chemical toxins that cannot be prevented by cell-death inhibitors. fatty acids containing more than one double bond in their backbone. type of small molecule-compounds including alpha-tocopherol, liproxstatin, and ferrostatin that can stop the process of lipid peroxidation at the level of lipid radicals. the 21st proteinogenic amino acid, differing from its analog cysteine only by the replacement of sulfur with selenium. a small family of 25 dedicated proteins in humans that contain the 21st, rare amino acid selenocysteine. a heterodimeric cystine/glutamate amino acid transporter comprising xCT (SLC7A11) and 4F2 (SLC3A2), importing cystine in cells while releasing one molecule of glutamate. also known as coenzyme Q10; a lipophilic metabolite derived from the mevalonate pathway that usually functions in the mitochondrial electron transport chain. Extramitochondrial CoQ10 regenerated by FSP1 acts like a strong RTA and regenerates vitamin E to prevent lipid peroxidation.