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Zheng, J. ; Conrad, M.

Ferroptosis: When metabolism meets cell death.

Physiol. Rev. 105, 651-706 (2024)
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We present here a comprehensive update on recent advancements in the field of ferroptosis, with a particular emphasis on its metabolic underpinnings and physiological impacts. After briefly introducing landmark studies that have helped to shape the concept of ferroptosis as a distinct form of cell death, we critically evaluate the key metabolic determinants involved in its regulation. These include the metabolism of essential trace elements such as selenium and iron; amino acids such as cyst(e)ine, methionine, glutamine/glutamate and tryptophan; and carbohydrates, covering glycolysis, the citric acid cycle, the electron transport chain and the pentose phosphate pathway. We also delve into the mevalonate pathway and subsequent cholesterol biosynthesis, including intermediate metabolites like dimethylallyl pyrophosphate, squalene, coenzyme Q (CoQ), vitamin K and 7-dehydrocholesterol, as well as fatty acid and phospholipid metabolism, including the biosynthesis and remodeling of ester and ether phospholipids and lipid peroxidation. Next, we highlight major ferroptosis surveillance systems, specifically the cyst(e)ine/glutathione/glutathione peroxidase 4 axis, the NAD(P)H/ferroptosis suppressor protein 1/CoQ/vitamin K system and the guanosine triphosphate cyclohydrolase 1/tetrahydrobiopterin/dihydrofolate reductase axis. We also discuss other potential anti- and pro-ferroptotic systems, including glutathione S-transferase P1, peroxiredoxin 6, dihydroorotate dehydrogenase, glycerol-3-phosphate dehydrogenase 2, vitamin K epoxide reductase complex subunit 1 like 1, nitric oxide and acyl-CoA synthetase long-chain family member 4. Finally, we explore ferroptosis's physiological roles in aging, tumor suppression and infection control, its pathological implications in tissue ischemia-reperfusion injury and neurodegeneration, and its potential therapeutic applications in cancer treatment. Existing drugs and compounds that may regulate ferroptosis in vivo are enumerated.
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Publication type Article: Journal article
Document type Review
Corresponding Author
Keywords Cancer Therapy ; Cell Metabolism ; Ferroptosis ; Pathology ; Physiology; Hydroperoxide Glutathione-peroxidase; Polyunsaturated Fatty-acids; Cystathionine Beta-synthase; X(c)(-) Cystine Transporter; Stress-induced Ferroptosis; Cisplatin-resistant Head; Neck-cancer Cells; Lipid-peroxidation; Selenoprotein-p; Oxidative-stress
ISSN (print) / ISBN 0031-9333
e-ISSN 1522-1210
Journal Physiological Reviews
Quellenangaben Volume: 105, Issue: 2, Pages: 651-706 Article Number: , Supplement: ,
Publisher American Physiological Society
Publishing Place 6120 Executive Blvd, Suite 600, Rockville, Md, United States
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Metabolism and Cell Death (MCD)
Grants European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program
DFG Priority Program
CRC
German Federal Ministry of Education and Research (BMBF) FERROPATH
Deutsche Forschungsgemeinschaft (DFG)