Ferroptosis#Mechanism

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.{{cite journal | vauthors = Murphy TH, Miyamoto M, Sastre A, Schnaar RL, Coyle JT | title = Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress | journal = Neuron | volume = 2 | issue = 6 | pages = 1547–1558 | date = June 1989 | pmid = 2576375 | doi = 10.1016/0896-6273(89)90043-3 }}{{cite journal | vauthors = Murphy TH, Schnaar RL, Coyle JT | title = Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake | journal = FASEB Journal | volume = 4 | issue = 6 | pages = 1624–1633 | date = April 1990 | pmid = 2180770 | doi = 10.1096/fasebj.4.6.2180770 | doi-access = free }} 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.{{cite journal | vauthors = Schubert D, Piasecki D | title = Oxidative glutamate toxicity can be a component of the excitotoxicity cascade | journal = The Journal of Neuroscience | volume = 21 | issue = 19 | pages = 7455–7462 | date = October 2001 | pmid = 11567035 | pmc = 6762876 | doi = 10.1523/JNEUROSCI.21-19-07455.2001 }}{{cite journal | vauthors = Tan S, Schubert D, Maher P | title = Oxytosis: A novel form of programmed cell death | journal = Current Topics in Medicinal Chemistry | volume = 1 | issue = 6 | pages = 497–506 | date = December 2001 | pmid = 11895126 | doi = 10.2174/1568026013394741 }}{{cite journal | vauthors = Tan S, Wood M, Maher P | title = Oxidative stress induces a form of programmed cell death with characteristics of both apoptosis and necrosis in neuronal cells | journal = Journal of Neurochemistry | volume = 71 | issue = 1 | pages = 95–105 | date = July 1998 | pmid = 9648855 | doi = 10.1046/j.1471-4159.1998.71010095.x }} 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.{{cite journal | vauthors = Lewerenz J, Ates G, Methner A, Conrad M, Maher P | title = Oxytosis/Ferroptosis-(Re-) Emerging Roles for Oxidative Stress-Dependent Non-apoptotic Cell Death in Diseases of the Central Nervous System | journal = Frontiers in Neuroscience | volume = 12 | pages = 214 | date = 2018 | pmid = 29731704 | pmc = 5920049 | doi = 10.3389/fnins.2018.00214 | doi-access = free }}{{cite journal | vauthors = Maher P, Currais A, Schubert D | title = Using the Oxytosis/Ferroptosis Pathway to Understand and Treat Age-Associated Neurodegenerative Diseases | journal = Cell Chemical Biology | volume = 27 | issue = 12 | pages = 1456–1471 | date = December 2020 | pmid = 33176157 | pmc = 7749085 | doi = 10.1016/j.chembiol.2020.10.010 }}

Other early studies regarding the connection between iron and lipid peroxidation,{{cite journal | vauthors = Gutteridge JM | title = Lipid peroxidation initiated by superoxide-dependent hydroxyl radicals using complexed iron and hydrogen peroxide | journal = FEBS Letters | volume = 172 | issue = 2 | pages = 245–249 | date = July 1984 | pmid = 6086389 | doi = 10.1016/0014-5793(84)81134-5 | s2cid = 22040840 | doi-access = free | bibcode = 1984FEBSL.172..245G }}{{cite journal | vauthors = Minotti G, Aust SD | title = The requirement for iron (III) in the initiation of lipid peroxidation by iron (II) and hydrogen peroxide | journal = The Journal of Biological Chemistry | volume = 262 | issue = 3 | pages = 1098–1104 | date = January 1987 | pmid = 3027077 | doi = 10.1016/S0021-9258(19)75755-X | doi-access = free }}{{cite journal | vauthors = Braughler JM, Duncan LA, Chase RL | title = The involvement of iron in lipid peroxidation. Importance of ferric to ferrous ratios in initiation | journal = The Journal of Biological Chemistry | volume = 261 | issue = 22 | pages = 10282–10289 | date = August 1986 | pmid = 3015924 | doi = 10.1016/S0021-9258(18)67521-0 | doi-access = free }}{{cite journal | vauthors = Minotti G, Aust SD | title = The role of iron in the initiation of lipid peroxidation | journal = Chemistry and Physics of Lipids | volume = 44 | issue = 2–4 | pages = 191–208 | date = 1987 | pmid = 2822270 | doi = 10.1016/0009-3084(87)90050-8 }}{{cite journal | vauthors = Minotti G | title = Sources and role of iron in lipid peroxidation | journal = Chemical Research in Toxicology | volume = 6 | issue = 2 | pages = 134–146 | date = 1993 | pmid = 8477003 | doi = 10.1021/tx00032a001 }} cystine deprivation and oxidative cell death,{{cite journal | vauthors = Eagle H | title = Nutrition needs of mammalian cells in tissue culture | journal = Science | volume = 122 | issue = 3168 | pages = 501–514 | date = September 1955 | pmid = 13255879 | doi = 10.1126/science.122.3168.501 | bibcode = 1955Sci...122..501E }}{{cite journal | vauthors = Eagle H, Piez KA, Oyama VI | title = The biosynthesis of cystine in human cell cultures | journal = The Journal of Biological Chemistry | volume = 236 | issue = 5 | pages = 1425–1428 | date = May 1961 | pmid = 13725478 | doi = 10.1016/S0021-9258(18)64190-0 | doi-access = free }}{{cite journal | vauthors = Yonezawa M, Back SA, Gan X, Rosenberg PA, Volpe JJ | title = Cystine deprivation induces oligodendroglial death: rescue by free radical scavengers and by a diffusible glial factor | journal = Journal of Neurochemistry | volume = 67 | issue = 2 | pages = 566–573 | date = August 1996 | pmid = 8764581 | doi = 10.1046/j.1471-4159.1996.67020566.x }}{{cite journal | vauthors = Ratan RR, Murphy TH, Baraban JM | title = Macromolecular synthesis inhibitors prevent oxidative stress-induced apoptosis in embryonic cortical neurons by shunting cysteine from protein synthesis to glutathione | journal = The Journal of Neuroscience | volume = 14 | issue = 7 | pages = 4385–4392 | date = July 1994 | pmid = 8027786 | pmc = 6577015 | doi = 10.1523/JNEUROSCI.14-07-04385.1994 }}{{cite journal | vauthors = Bannai S, Tsukeda H, Okumura H | title = Effect of antioxidants on cultured human diploid fibroblasts exposed to cystine-free medium | journal = Biochemical and Biophysical Research Communications | volume = 74 | issue = 4 | pages = 1582–1588 | date = February 1977 | pmid = 843380 | doi = 10.1016/0006-291x(77)90623-4 }} the activity and importance of glutathione peroxidase 4 (GPX4),{{cite journal | vauthors = Ursini F, Maiorino M, Valente M, Ferri L, Gregolin C | title = Purification from pig liver of a protein which protects liposomes and biomembranes from peroxidative degradation and exhibits glutathione peroxidase activity on phosphatidylcholine hydroperoxides | journal = Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism | volume = 710 | issue = 2 | pages = 197–211 | date = February 1982 | pmid = 7066358 | doi = 10.1016/0005-2760(82)90150-3 }}{{cite journal | vauthors = Ursini F, Maiorino M, Gregolin C | title = The selenoenzyme phospholipid hydroperoxide glutathione peroxidase | journal = Biochimica et Biophysica Acta (BBA) - General Subjects | volume = 839 | issue = 1 | pages = 62–70 | date = March 1985 | pmid = 3978121 | doi = 10.1016/0304-4165(85)90182-5 }}{{cite journal | vauthors = Yant LJ, Ran Q, Rao L, Van Remmen H, Shibatani T, Belter JG, Motta L, Richardson A, Prolla TA | title = The selenoprotein GPX4 is essential for mouse development and protects from radiation and oxidative damage insults | journal = Free Radical Biology & Medicine | volume = 34 | issue = 4 | pages = 496–502 | date = February 2003 | pmid = 12566075 | doi = 10.1016/S0891-5849(02)01360-6 }}{{cite journal | vauthors = Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, Plesnila N, Kremmer E, Rådmark O, Wurst W, Bornkamm GW, Schweizer U, Conrad M | title = Glutathione peroxidase 4 senses and translates oxidative stress into 12/15-lipoxygenase dependent- and AIF-mediated cell death | journal = Cell Metabolism | volume = 8 | issue = 3 | pages = 237–248 | date = September 2008 | pmid = 18762024 | doi = 10.1016/j.cmet.2008.07.005 | doi-access = free }}{{cite journal | vauthors = Mannes AM, Seiler A, Bosello V, Maiorino M, Conrad M | title = Cysteine mutant of mammalian GPx4 rescues cell death induced by disruption of the wild-type selenoenzyme | journal = FASEB Journal | volume = 25 | issue = 7 | pages = 2135–2144 | date = July 2011 | pmid = 21402720 | doi = 10.1096/fj.10-177147 | doi-access = free }} and the identification of small molecules that induce ferroptosis{{cite journal | vauthors = Dolma S, Lessnick SL, Hahn WC, Stockwell BR | title = Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells | journal = Cancer Cell | volume = 3 | issue = 3 | pages = 285–296 | date = March 2003 | pmid = 12676586 | doi = 10.1016/s1535-6108(03)00050-3 | doi-access = free }}{{cite journal | vauthors = Yagoda N, von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, Wolpaw AJ, Smukste I, Peltier JM, Boniface JJ, Smith R, Lessnick SL, Sahasrabudhe S, Stockwell BR | title = RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels | journal = Nature | volume = 447 | issue = 7146 | pages = 864–868 | date = June 2007 | pmid = 17568748 | pmc = 3047570 | doi = 10.1038/nature05859 | bibcode = 2007Natur.447..865Y }}{{cite journal | vauthors = Yang WS, Stockwell BR | title = Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells | journal = Chemistry & Biology | volume = 15 | issue = 3 | pages = 234–245 | date = March 2008 | pmid = 18355723 | pmc = 2683762 | doi = 10.1016/j.chembiol.2008.02.010 }} were key to the eventual characterization of ferroptosis.

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.{{cite journal | vauthors = Mai TT, Hamaï A, Hienzsch A, Cañeque T, Müller S, Wicinski J, Cabaud O, Leroy C, David A, Acevedo V, Ryo A, Ginestier C, Birnbaum D, Charafe-Jauffret E, Codogno P, Mehrpour M, Rodriguez R | title = Salinomycin kills cancer stem cells by sequestering iron in lysosomes | journal = Nature Chemistry | volume = 9 | issue = 10 | pages = 1025–1033 | date = October 2017 | pmid = 28937680 | pmc = 5890907 | doi = 10.1038/nchem.2778 | bibcode = 2017NatCh...9.1025M }} Ferroptosis has been shown to involve distinct cellular organelles,{{Cite journal |last1=Chen |first1=Xin |last2=Kang |first2=Rui |last3=Kroemer |first3=Guido |last4=Tang |first4=Daolin |date=October 2021 |title=Organelle-specific regulation of ferroptosis |url=https://www.nature.com/articles/s41418-021-00859-z |journal=Cell Death & Differentiation |language=en |volume=28 |issue=10 |pages=2843–2856 |doi=10.1038/s41418-021-00859-z |issn=1476-5403|pmc=8481335 }} which includes peroxisomes,{{Cite journal |last1=Zou |first1=Yilong |last2=Henry |first2=Whitney S. |last3=Ricq |first3=Emily L. |last4=Graham |first4=Emily T. |last5=Phadnis |first5=Vaishnavi V. |last6=Maretich |first6=Pema |last7=Paradkar |first7=Sateja |last8=Boehnke |first8=Natalie |last9=Deik |first9=Amy A. |last10=Reinhardt |first10=Ferenc |last11=Eaton |first11=John K. |last12=Ferguson |first12=Bryan |last13=Wang |first13=Wenyu |last14=Fairman |first14=Joshua |last15=Keys |first15=Heather R. |date=September 2020 |title=Plasticity of ether lipids promotes ferroptosis susceptibility and evasion |journal=Nature |language=en |volume=585 |issue=7826 |pages=603–608 |doi=10.1038/s41586-020-2732-8 |pmid=32939090 |pmc=8051864 |bibcode=2020Natur.585..603Z |issn=1476-4687}} mitochondria,{{Cite journal |last1=Gao |first1=Minghui |last2=Yi |first2=Junmei |last3=Zhu |first3=Jiajun |last4=Minikes |first4=Alexander M. |last5=Monian |first5=Prashant |last6=Thompson |first6=Craig B. |last7=Jiang |first7=Xuejun |date=2019-01-17 |title=Role of Mitochondria in Ferroptosis |url=https://www.cell.com/molecular-cell/fulltext/S1097-2765(18)30936-5 |journal=Molecular Cell |language=English |volume=73 |issue=2 |pages=354–363.e3 |doi=10.1016/j.molcel.2018.10.042 |issn=1097-2765 |pmid=30581146|pmc=6338496 }} the endoplasmic reticulum (ER){{Cite journal |last1=Dixon |first1=Scott J |last2=Patel |first2=Darpan N |last3=Welsch |first3=Matthew |last4=Skouta |first4=Rachid |last5=Lee |first5=Eric D |last6=Hayano |first6=Miki |last7=Thomas |first7=Ajit G |last8=Gleason |first8=Caroline E |last9=Tatonetti |first9=Nicholas P |last10=Slusher |first10=Barbara S |last11=Stockwell |first11=Brent R |date=2014-05-20 |editor-last=van der Donk |editor-first=Wilfred |title=Pharmacological inhibition of cystine–glutamate exchange induces endoplasmic reticulum stress and ferroptosis |url=https://elifesciences.org/articles/02523 |journal=eLife |volume=3 |pages=e02523 |doi=10.7554/eLife.02523 |doi-access=free |pmid=24844246 |issn=2050-084X|pmc=4054777 }} and lysosomes.{{Cite journal |last1=Mai |first1=Trang Thi |last2=Hamaï |first2=Ahmed |last3=Hienzsch |first3=Antje |last4=Cañeque |first4=Tatiana |last5=Müller |first5=Sebastian |last6=Wicinski |first6=Julien |last7=Cabaud |first7=Olivier |last8=Leroy |first8=Christine |last9=David |first9=Amandine |last10=Acevedo |first10=Verónica |last11=Ryo |first11=Akihide |last12=Ginestier |first12=Christophe |last13=Birnbaum |first13=Daniel |last14=Charafe-Jauffret |first14=Emmanuelle |last15=Codogno |first15=Patrice |date=October 2017 |title=Salinomycin kills cancer stem cells by sequestering iron in lysosomes |journal=Nature Chemistry |language=en |volume=9 |issue=10 |pages=1025–1033 |doi=10.1038/nchem.2778 |pmid=28937680 |pmc=5890907 |bibcode=2017NatCh...9.1025M |issn=1755-4349}}{{Cite journal |last1=Torii |first1=Seiji |last2=Shintoku |first2=Ryosuke |last3=Kubota |first3=Chisato |last4=Yaegashi |first4=Makoto |last5=Torii |first5=Ryoko |last6=Sasaki |first6=Masaya |last7=Suzuki |first7=Toshinobu |last8=Mori |first8=Masanobu |last9=Yoshimoto |first9=Yuhei |last10=Takeuchi |first10=Toshiyuki |last11=Yamada |first11=Keiichi |date=2016-03-10 |title=An essential role for functional lysosomes in ferroptosis of cancer cells |url=https://portlandpress.com/biochemj/article-abstract/473/6/769/49342/An-essential-role-for-functional-lysosomes-in?redirectedFrom=fulltext |journal=Biochemical Journal |volume=473 |issue=6 |pages=769–777 |doi=10.1042/BJ20150658 |issn=0264-6021}}{{Cite journal |last1=Cañeque |first1=Tatiana |last2=Baron |first2=Leeroy |last3=Müller |first3=Sebastian |last4=Carmona |first4=Alanis |last5=Colombeau |first5=Ludovic |last6=Versini |first6=Antoine |last7=Solier |first7=Stéphanie |last8=Gaillet |first8=Christine |last9=Sindikubwabo |first9=Fabien |last10=Sampaio |first10=Julio L. |last11=Sabatier |first11=Marie |last12=Mishima |first12=Eikan |last13=Picard-Bernes |first13=Armel |last14=Syx |first14=Laurène |last15=Servant |first15=Nicolas |date=2025-05-07 |title=Activation of lysosomal iron triggers ferroptosis in cancer |url=https://www.nature.com/articles/s41586-025-08974-4 |journal=Nature |language=en |pages=1–9 |doi=10.1038/s41586-025-08974-4 |pmid=40335696 |issn=1476-4687|doi-access=free }} It has been a debate in the scientific community, where ferroptosis is initiated in the cell, and now research points to the lysosome,{{Cite journal |last1=Cañeque |first1=Tatiana |last2=Baron |first2=Leeroy |last3=Müller |first3=Sebastian |last4=Carmona |first4=Alanis |last5=Colombeau |first5=Ludovic |last6=Versini |first6=Antoine |last7=Solier |first7=Stéphanie |last8=Gaillet |first8=Christine |last9=Sindikubwabo |first9=Fabien |last10=Sampaio |first10=Julio L. |last11=Sabatier |first11=Marie |last12=Mishima |first12=Eikan |last13=Picard-Bernes |first13=Armel |last14=Syx |first14=Laurène |last15=Servant |first15=Nicolas |date=2025-05-07 |title=Activation of lysosomal iron triggers ferroptosis in cancer |url=https://www.nature.com/articles/s41586-025-08974-4 |journal=Nature |language=en |pages=1–9 |doi=10.1038/s41586-025-08974-4 |pmid=40335696 |issn=1476-4687|doi-access=free }} where the chemical environment (iron, pH an hydrogen peroxide) are favorable. Oxidation of phospholipids can occur when free radicals abstract electrons from a lipid molecule (typically affecting polyunsaturated fatty acids), 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.{{cite journal | vauthors = Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K, Roveri A, Peng X, Porto Freitas F, Seibt T, Mehr L, Aichler M, Walch A, Lamp D, Jastroch M, Miyamoto S, Wurst W, Ursini F, Arnér ES, Fradejas-Villar N, Schweizer U, Zischka H, Friedmann Angeli JP, Conrad M | title = Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis | journal = Cell | volume = 172 | issue = 3 | pages = 409–422.e21 | date = January 2018 | pmid = 29290465 | doi = 10.1016/j.cell.2017.11.048 | hdl-access = free | hdl = 11577/3255195 }} Recently, a second parallel protective pathway was independently discovered by two labs that involves the oxidoreductase FSP1 (also known as AIFM2).{{cite journal | vauthors = Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, Roberts MA, Tong B, Maimone TJ, Zoncu R, Bassik MC, Nomura DK, Dixon SJ, Olzmann JA | title = The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis | journal = Nature | volume = 575 | issue = 7784 | pages = 688–692 | date = November 2019 | pmid = 31634900 | pmc = 6883167 | doi = 10.1038/s41586-019-1705-2 | bibcode = 2019Natur.575..688B }}{{cite journal | vauthors = Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, Goya Grocin A, Xavier da Silva TN, Panzilius E, Scheel CH, Mourão A, Buday K, Sato M, Wanninger J, Vignane T, Mohana V, Rehberg M, Flatley A, Schepers A, Kurz A, White D, Sauer M, Sattler M, Tate EW, Schmitz W, Schulze A, O'Donnell V, Proneth B, Popowicz GM, Pratt DA, Angeli JP, Conrad M | title = FSP1 is a glutathione-independent ferroptosis suppressor | journal = Nature | volume = 575 | issue = 7784 | pages = 693–698 | date = November 2019 | pmid = 31634899 | doi = 10.1038/s41586-019-1707-0 | hdl-access = free | s2cid = 204833583 | bibcode = 2019Natur.575..693D | hdl = 10044/1/75345 | url = https://orca.cardiff.ac.uk/id/eprint/126674/ }} FSP1 enzymatically reduces non-mitochondrial coenzyme Q₁₀ (CoQ₁₀), 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.{{cite journal | vauthors = Mishima E, Ito J, Wu Z, Nakamura T, Wahida A, Doll S, Tonnus W, Nepachalovich P, Eggenhofer E, Aldrovandi M, Henkelmann B, Yamada KI, Wanninger J, Zilka O, Sato E, Feederle R, Hass D, Maida A, Mourão AS, Linkermann A, Geissler EK, Nakagawa K, Abe T, Fedorova M, Proneth B, Pratt DA, Conrad M | title = A non-canonical vitamin K cycle is a potent ferroptosis suppressor | journal = Nature | volume = 608 | issue = 7924 | pages = 778–783 | date = August 2022 | pmid = 35922516 | pmc = 9402432 | doi = 10.1038/s41586-022-05022-3 | bibcode = 2022Natur.608..778M }} A similar mechanism for a cofactor moonlighting as a diffusable antioxidant was discovered in the same year for tetrahydrobiopterin (BH₄), a product of the rate-limiting enzyme GTP cyclohdrolase 1 (GCH1).{{cite journal | vauthors = Kraft VA, Bezjian CT, Pfeiffer S, Ringelstetter L, Müller C, Zandkarimi F, Merl-Pham J, Bao X, Anastasov N, Kössl J, Brandner S, Daniels JD, Schmitt-Kopplin P, Hauck SM, Stockwell BR, Hadian K, Schick JA | title = GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling | journal = ACS Central Science | volume = 6 | issue = 1 | pages = 41–53 | date = January 2020 | pmid = 31989025 | pmc = 6978838 | doi = 10.1021/acscentsci.9b01063 }}{{cite journal | vauthors = Soula M, Weber RA, Zilka O, Alwaseem H, La K, Yen F, Molina H, Garcia-Bermudez J, Pratt DA, Birsoy K | title = Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers | journal = Nature Chemical Biology | volume = 16 | issue = 12 | pages = 1351–1360 | date = December 2020 | pmid = 32778843 | pmc = 8299533 | doi = 10.1038/s41589-020-0613-y }}

File:Ferroptosis human prostate cancer model.gif

Replacing natural polyunsaturated fatty acids (PUFA) with deuterated PUFA (dPUFA), which have deuterium in place of the bis-allylic hydrogens, can prevent cell death induced by erastin or RSL3.{{cite journal | vauthors = Bartolacci C, Andreani C, El-Gammal Y, Scaglioni PP | title = Lipid Metabolism Regulates Oxidative Stress and Ferroptosis in RAS-Driven Cancers: A Perspective on Cancer Progression and Therapy | journal = Frontiers in Molecular Biosciences | volume = 8 | pages = 706650 | date = 2021 | pmid = 34485382 | pmc = 8415548 | doi = 10.3389/fmolb.2021.706650 | doi-access = free }} These deuterated PUFAs effectively inhibit ferroptosis and various chronic degenerative diseases associated with ferroptosis.{{cite journal | vauthors = Jiang X, Stockwell BR, Conrad M | title = Ferroptosis: mechanisms, biology and role in disease | journal = Nature Reviews. Molecular Cell Biology | volume = 22 | issue = 4 | pages = 266–282 | date = April 2021 | pmid = 33495651 | pmc = 8142022 | doi = 10.1038/s41580-020-00324-8 }}

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 (see GIF on right side). {{citation needed|date=November 2024}}

Ferroptosis was initially characterized in human cell lines and has been since found to occur in other mammals (mice),{{cite journal | vauthors = Friedmann Angeli JP, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, Herbach N, Aichler M, Walch A, Eggenhofer E, Basavarajappa D, Rådmark O, Kobayashi S, Seibt T, Beck H, Neff F, Esposito I, Wanke R, Förster H, Yefremova O, Heinrichmeyer M, Bornkamm GW, Geissler EK, Thomas SB, Stockwell BR, O'Donnell VB, Kagan VE, Schick JA, Conrad M | title = Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice | journal = Nature Cell Biology | volume = 16 | issue = 12 | pages = 1180–1191 | date = December 2014 | pmid = 25402683 | pmc = 4894846 | doi = 10.1038/ncb3064 }} avians (chicken), worms (C. elegans),{{cite journal | vauthors = Jenkins NL, James SA, Salim A, Sumardy F, Speed TP, Conrad M, Richardson DR, Bush AI, McColl G | title = Changes in ferrous iron and glutathione promote ferroptosis and frailty in aging Caenorhabditis elegans | journal = eLife | volume = 9 | pages = e56580 | date = July 2020 | pmid = 32690135 | pmc = 7373428 | doi = 10.7554/eLife.56580 | veditors = Tyler J, Gruber JT | doi-access = free }}{{cite journal | vauthors = Perez MA, Magtanong L, Dixon SJ, Watts JL | title = Dietary Lipids Induce Ferroptosis in Caenorhabditiselegans and Human Cancer Cells | language = English | journal = Developmental Cell | volume = 54 | issue = 4 | pages = 447–454.e4 | date = August 2020 | pmid = 32652074 | pmc = 7483868 | doi = 10.1016/j.devcel.2020.06.019 }} and plants (A. thaliana,{{cite journal | vauthors = Distéfano AM, Martin MV, Córdoba JP, Bellido AM, D'Ippólito S, Colman SL, Soto D, Roldán JA, Bartoli CG, Zabaleta EJ, Fiol DF, Stockwell BR, Dixon SJ, Pagnussat GC | title = Heat stress induces ferroptosis-like cell death in plants | journal = The Journal of Cell Biology | volume = 216 | issue = 2 | pages = 463–476 | date = February 2017 | pmid = 28100685 | pmc = 5294777 | doi = 10.1083/jcb.201605110 }}{{cite journal | vauthors = Li J, Chen S, Huang J, Chen H, Chen Z, Wen Y | title = New Target in an Old Enemy: Herbicide (R)-Dichlorprop Induces Ferroptosis-like Death in Plants | journal = Journal of Agricultural and Food Chemistry | volume = 69 | issue = 27 | pages = 7554–7564 | date = July 2021 | pmid = 34196530 | doi = 10.1021/acs.jafc.1c02102 | bibcode = 2021JAFC...69.7554L }} T. aestivum L.,{{cite journal | vauthors = Kalaipandian S, Powell J, Karunakaran A, Stiller J, Adkins S, Kage U, Kazan K, Fleury D | title = Transcriptome Analysis of Heat Shock Factor C2a Over-Expressing Wheat Roots Reveals Ferroptosis-like Cell Death in Heat Stress Recovery | journal = International Journal of Molecular Sciences | volume = 24 | issue = 4 | pages = 3099 | date = February 2023 | pmid = 36834507 | pmc = 9967677 | doi = 10.3390/ijms24043099 | doi-access = free }} and others).{{cite journal | vauthors = Cheng Y, Zhang H, Zhu W, Li Q, Meng R, Yang K, Guo Z, Zhai Y, Zhang H, Ji R, Peng H, Dou D, Jing M | title = Ferroptosis induced by the biocontrol agent Pythium oligandrum enhances soybean resistance to Phytophthora sojae | journal = Environmental Microbiology | volume = 24 | issue = 12 | pages = 6267–6278 | date = December 2022 | pmid = 36250814 | doi = 10.1111/1462-2920.16248 | bibcode = 2022EnvMi..24.6267C }}{{cite journal | vauthors = Nguyen NK, Wang J, Liu D, Hwang BK, Jwa NS | title = Rice iron storage protein ferritin 2 (OsFER2) positively regulates ferroptotic cell death and defense responses against Magnaporthe oryzae | journal = Frontiers in Plant Science | volume = 13 | pages = 1019669 | date = 2022 | pmid = 36352872 | pmc = 9639352 | doi = 10.3389/fpls.2022.1019669 | doi-access = free | bibcode = 2022FrPS...1319669N }}{{cite journal | vauthors = Chen Y, Wang J, Nguyen NK, Hwang BK, Jwa NS | title = The NIN-Like Protein OsNLP2 Negatively Regulates Ferroptotic Cell Death and Immune Responses to Magnaporthe oryzae in Rice | journal = Antioxidants | volume = 11 | issue = 9 | pages = 1795 | date = September 2022 | pmid = 36139868 | pmc = 9495739 | doi = 10.3390/antiox11091795 | doi-access = free }}{{cite journal | vauthors = Hajdinák P, Czobor Á, Szarka A | title = The potential role of acrolein in plant ferroptosis-like cell death | journal = PLOS ONE | volume = 14 | issue = 12 | pages = e0227278 | date = 2019 | pmid = 31887216 | pmc = 6936820 | doi = 10.1371/journal.pone.0227278 | doi-access = free | bibcode = 2019PLoSO..1427278H }} Ferroptosis has also been demonstrated in canine cancer cell models.{{cite journal | vauthors = Chatterji P, Xing G, Furst L, Dave K, Zhou Q, LaBarbera DV, Thamm DH, Eaton JK, Wawer MJ, Viswanathan VS | title = Validation of ferroptosis in canine cancer cells to enable comparative oncology and translational medicine | journal = bioRxiv | pages = 2024.04.28.591561 | date = April 2024 | pmid = 38746359 | pmc = 11092520 | doi = 10.1101/2024.04.28.591561 }} There have been limited studies in other model organisms such as D. melanogaster.{{cite journal | vauthors = Agostini F, Bubacco L, Chakrabarti S, Bisaglia M | title = α-Synuclein Toxicity in Drosophila melanogaster Is Enhanced by the Presence of Iron: Implications for Parkinson's Disease | journal = Antioxidants | volume = 12 | issue = 2 | pages = 261 | date = January 2023 | pmid = 36829820 | pmc = 9952566 | doi = 10.3390/antiox12020261 | doi-access = free }}{{cite journal | vauthors = Wang YQ, Chang SY, Wu Q, Gou YJ, Jia L, Cui YM, Yu P, Shi ZH, Wu WS, Gao G, Chang YZ | title = The Protective Role of Mitochondrial Ferritin on Erastin-Induced Ferroptosis | journal = Frontiers in Aging Neuroscience | volume = 8 | pages = 308 | date = 2016 | pmid = 28066232 | pmc = 5167726 | doi = 10.3389/fnagi.2016.00308 | doi-access = free }} 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.{{cite journal | vauthors = Conrad M, Kagan VE, Bayir H, Pagnussat GC, Head B, Traber MG, Stockwell BR | title = Regulation of lipid peroxidation and ferroptosis in diverse species | journal = Genes & Development | volume = 32 | issue = 9–10 | pages = 602–619 | date = May 2018 | pmid = 29802123 | pmc = 6004068 | doi = 10.1101/gad.314674.118 }}{{cite journal | vauthors = Aguilera A, Berdun F, Bartoli C, Steelheart C, Alegre M, Bayir H, Tyurina YY, Kagan VE, Salerno G, Pagnussat G, Martin MV | title = C-ferroptosis is an iron-dependent form of regulated cell death in cyanobacteria | journal = The Journal of Cell Biology | volume = 221 | issue = 2 | pages = e201911005 | date = February 2022 | pmid = 34817556 | pmc = 8624678 | doi = 10.1083/jcb.201911005 }} 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.

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.{{cite journal | vauthors = Saunders JW | title = Death in embryonic systems | journal = Science | volume = 154 | issue = 3749 | pages = 604–612 | date = November 1966 | pmid = 5332319 | doi = 10.1126/science.154.3749.604 | bibcode = 1966Sci...154..604S }}{{cite journal | vauthors = Ghose P, Shaham S | title = Cell death in animal development | journal = Development | volume = 147 | issue = 14 | pages = dev191882 | date = July 2020 | pmid = 32709690 | pmc = 7390631 | doi = 10.1242/dev.191882 }} 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.{{cite journal | vauthors = Co HK, Wu CC, Lee YC, Chen SH | title = Emergence of large-scale cell death through ferroptotic trigger waves | journal = Nature | volume = 631 | issue = 8021 | pages = 654–662 | date = July 2024 | pmid = 38987590 | pmc = 11639682 | doi = 10.1038/s41586-024-07623-6 | bibcode = 2024Natur.631..654C }} The exact pro-ferroptotic signal that is transmitted between cells and the manner by which these ferroptotic waves are bounded remain to be characterized.

File:Initiation of Ferroptosis By Inhibition of Xc- System of Gpx4 Activity.jpeg activity]]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.{{Cite web |title=Our Pipeline |url=https://kojintx.com/}}{{Cite web |title=OUR SCIENCE: Ferroptosis & Inflammation – Targeting oxidative stress and inflammation pathways to treat CNS diseases |url=https://www.ptcbio.com/our-science/ferroptosis-and-inflammation/}}{{Citation | vauthors = Eaton JK, Chatterji P, Furst L, Basak S, Patel AM, Sweat YY, Cai LL, Dave K, Victoria RA, Pizzi E, Noorbakhsh J |title=The enzyme glutamate-cysteine ligase (GCL) is a target for ferroptosis induction in cancer |date=2024-04-30 |url=https://www.biorxiv.org/content/10.1101/2024.04.28.591552v1 |access-date=2024-12-27 |language=en |doi=10.1101/2024.04.28.591552 |doi-access=free }} Ferroptosis has been implicated in a range of different diseases including cancer, ischemia/reperfusion injury (IRI), inflammation, neurodegeneration, and kidney injury.{{cite journal | vauthors = Berndt C, Alborzinia H, Amen VS, Ayton S, Barayeu U, Bartelt A, Bayir H, Bebber CM, Birsoy K, Böttcher JP, Brabletz S, Brabletz T, Brown AR, Brüne B, Bulli G, Bruneau A, Chen Q, DeNicola GM, Dick TP, Distéfano A, Dixon SJ, Engler JB, Esser-von Bieren J, Fedorova M, Friedmann Angeli JP, Friese MA, Fuhrmann DC, García-Sáez AJ, Garbowicz K, Götz M, Gu W, Hammerich L, Hassannia B, Jiang X, Jeridi A, Kang YP, Kagan VE, Konrad DB, Kotschi S, Lei P, Le Tertre M, Lev S, Liang D, Linkermann A, Lohr C, Lorenz S, Luedde T, Methner A, Michalke B, Milton AV, Min J, Mishima E, Müller S, Motohashi H, Muckenthaler MU, Murakami S, Olzmann JA, Pagnussat G, Pan Z, Papagiannakopoulos T, Pedrera Puentes L, Pratt DA, Proneth B, Ramsauer L, Rodriguez R, Saito Y, Schmidt F, Schmitt C, Schulze A, Schwab A, Schwantes A, Soula M, Spitzlberger B, Stockwell BR, Thewes L, Thorn-Seshold O, Toyokuni S, Tonnus W, Trumpp A, Vandenabeele P, Vanden Berghe T, Venkataramani V, Vogel FC, von Karstedt S, Wang F, Westermann F, Wientjens C, Wilhelm C, Wölk M, Wu K, Yang X, Yu F, Zou Y, Conrad M | title = Ferroptosis in health and disease | journal = Redox Biology | volume = 75 | pages = 103211 | date = September 2024 | pmid = 38908072 | pmc = 11253697 | doi = 10.1016/j.redox.2024.103211 }}

Ferroptosis has been explored as a strategy to selectively kill cancer cells.{{cite journal | vauthors = Lei G, Zhuang L, Gan B | title = Targeting ferroptosis as a vulnerability in cancer | journal = Nature Reviews. Cancer | volume = 22 | issue = 7 | pages = 381–396 | date = July 2022 | pmid = 35338310 | pmc = 10243716 | doi = 10.1038/s41568-022-00459-0 }}

Oxytosis/ferroptosis has been implicated in several types of cancer, including:{{citation needed|date=November 2024}}

• Breast
• Acute myeloid leukemia
• Pancreatic ductal adenocarcinoma
• Ovarian
• B-cell lymphoma
• Renal cell carcinomas
• Lung
• Glioblastoma

These forms of cancer have been hypothesized to be highly sensitive to oxytosis/ferroptosis induction. An upregulation of iron levels has also been seen to induce oxytosis/ferroptosis in certain types of cancer, such as breast cancer. Breast cancer cells have exhibited vulnerability to oxytosis/ferroptosis via a combination of siramesine and lapatinib. These cells also exhibited an autophagic cycle independent of ferroptotic activity, indicating that the two different forms of cell death could be controlled to activate at specific times following treatment.{{cite journal | vauthors = Ma S, Dielschneider RF, Henson ES, Xiao W, Choquette TR, Blankstein AR, Chen Y, Gibson SB | title = Ferroptosis and autophagy induced cell death occur independently after siramesine and lapatinib treatment in breast cancer cells | journal = PLOS ONE | volume = 12 | issue = 8 | pages = e0182921 | year = 2017 | pmid = 28827805 | pmc = 5565111 | doi = 10.1371/journal.pone.0182921 | doi-access = free | bibcode = 2017PLoSO..1282921M }} Furthermore, intratumor bacteria may scavenge iron by producing iron siderophores, which indirectly protect tumor cells from ferroptosis, emphasizing the need for ferroptosis inducers (thiostrepton) for cancer treatment.{{cite journal | vauthors = Yeung YW, Ma Y, Deng Y, Khoo BL, Chua SL | title = Bacterial Iron Siderophore Drives Tumor Survival and Ferroptosis Resistance in a Biofilm-Tumor Spheroid Coculture Model | journal = Advanced Science | volume = 11 | issue = 39 | pages = e2404467 | date = October 2024 | pmid = 39135304 | pmc = 11496991 | doi = 10.1002/advs.202404467 | doi-access = free }}

In various contexts, resistance to cancer therapy is associated with a mesenchymal state.{{cite journal | vauthors = Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu CC, LeBleu VS, Kalluri R | title = Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer | journal = Nature | volume = 527 | issue = 7579 | pages = 525–530 | date = November 2015 | pmid = 26560028 | pmc = 4849281 | doi = 10.1038/nature16064 | bibcode = 2015Natur.527..525Z }}{{cite journal | vauthors = Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, Choi H, El Rayes T, Ryu S, Troeger J, Schwabe RF, Vahdat LT, Altorki NK, Mittal V, Gao D | title = Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance | journal = Nature | volume = 527 | issue = 7579 | pages = 472–476 | date = November 2015 | pmid = 26560033 | pmc = 4662610 | doi = 10.1038/nature15748 | bibcode = 2015Natur.527..472F }}{{cite journal | vauthors = Shibue T, Weinberg RA | title = EMT, CSCs, and drug resistance: the mechanistic link and clinical implications | journal = Nature Reviews. Clinical Oncology | volume = 14 | issue = 10 | pages = 611–629 | date = October 2017 | pmid = 28397828 | pmc = 5720366 | doi = 10.1038/nrclinonc.2017.44 }} 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.{{cite journal | vauthors = Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, Galeas J, Dhruv HD, Berens ME, Schreiber SL, McCormick F, McManus MT | title = Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition | journal = Nature | volume = 551 | issue = 7679 | pages = 247–250 | date = November 2017 | pmid = 29088702 | pmc = 5933935 | doi = 10.1038/nature24297 | bibcode = 2017Natur.551..247H }}{{cite journal | vauthors = Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, Kaffenberger SD, Eaton JK, Shimada K, Aguirre AJ, Viswanathan SR, Chattopadhyay S, Tamayo P, Yang WS, Rees MG, Chen S, Boskovic ZV, Javaid S, Huang C, Wu X, Tseng YY, Roider EM, Gao D, Cleary JM, Wolpin BM, Mesirov JP, Haber DA, Engelman JA, Boehm JS, Kotz JD, Hon CS, Chen Y, Hahn WC, Levesque MP, Doench JG, Berens ME, Shamji AF, Clemons PA, Stockwell BR, Schreiber SL | title = Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway | journal = Nature | volume = 547 | issue = 7664 | pages = 453–457 | date = July 2017 | pmid = 28678785 | pmc = 5667900 | doi = 10.1038/nature23007 }}

File:Induction of Neurodegeneration by Ferroptosis.jpeg

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.{{cite journal | vauthors = Hambright WS, Fonseca RS, Chen L, Na R, Ran Q | title = Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration | journal = Redox Biology | volume = 12 | pages = 8–17 | date = August 2017 | pmid = 28212525 | pmc = 5312549 | doi = 10.1016/j.redox.2017.01.021 }} More recently, oxytosis/ferroptosis has been linked to diverse brain diseases,{{cite journal | vauthors = Weiland A, Wang Y, Wu W, Lan X, Han X, Li Q, Wang J | title = Ferroptosis and Its Role in Diverse Brain Diseases | journal = Molecular Neurobiology | volume = 56 | issue = 7 | pages = 4880–4893 | date = July 2019 | pmid = 30406908 | pmc = 6506411 | doi = 10.1007/s12035-018-1403-3 }} in particular, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease.{{cite journal | vauthors = Ryan SK, Ugalde CL, Rolland AS, Skidmore J, Devos D, Hammond TR | title = Therapeutic inhibition of ferroptosis in neurodegenerative disease | journal = Trends in Pharmacological Sciences | volume = 44 | issue = 10 | pages = 674–688 | date = October 2023 | pmid = 37657967 | doi = 10.1016/j.tips.2023.07.007 | doi-access = free }} Two new studies show that oxytosis/ferroptosis contributes to neuronal death after intracerebral hemorrhage.{{cite journal | vauthors = Li Q, Han X, Lan X, Gao Y, Wan J, Durham F, Cheng T, Yang J, Wang Z, Jiang C, Ying M, Koehler RC, Stockwell BR, Wang J | title = Inhibition of neuronal ferroptosis protects hemorrhagic brain | journal = JCI Insight | volume = 2 | issue = 7 | pages = e90777 | date = April 2017 | pmid = 28405617 | pmc = 5374066 | doi = 10.1172/jci.insight.90777 }}{{cite journal | vauthors = Li Q, Weiland A, Chen X, Lan X, Han X, Durham F, Liu X, Wan J, Ziai WC, Hanley DF, Wang J | title = Ultrastructural Characteristics of Neuronal Death and White Matter Injury in Mouse Brain Tissues After Intracerebral Hemorrhage: Coexistence of Ferroptosis, Autophagy, and Necrosis | journal = Frontiers in Neurology | volume = 9 | pages = 581 | date = July 2018 | pmid = 30065697 | pmc = 6056664 | doi = 10.3389/fneur.2018.00581 | doi-access = free }} 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.{{citation needed|date=November 2024}}

Recent studies have suggested that oxytosis/ferroptosis contributes to neuronal cell death after traumatic brain injury.{{cite journal | vauthors = Qin D, Wang J, Le A, Wang TJ, Chen X, Wang J | title = Traumatic Brain Injury: Ultrastructural Features in Neuronal Ferroptosis, Glial Cell Activation and Polarization, and Blood-Brain Barrier Breakdown | journal = Cells | volume = 10 | issue = 5 | pages = 1009 | date = April 2021 | pmid = 33923370 | pmc = 8146242 | doi = 10.3390/cells10051009 | doi-access = free }}

Ferroptosis occurs during acute kidney injury in various cellular and animal models.{{cite journal | vauthors = Skouta R, Dixon SJ, Wang J, Dunn DE, Orman M, Shimada K, Rosenberg PA, Lo DC, Weinberg JM, Linkermann A, Stockwell BR | title = Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models | journal = Journal of the American Chemical Society | volume = 136 | issue = 12 | pages = 4551–4556 | date = March 2014 | pmid = 24592866 | pmc = 3985476 | doi = 10.1021/ja411006a | bibcode = 2014JAChS.136.4551S }}{{cite journal | vauthors = Linkermann A, Skouta R, Himmerkus N, Mulay SR, Dewitz C, De Zen F, Prokai A, Zuchtriegel G, Krombach F, Welz PS, Weinlich R, Vanden Berghe T, Vandenabeele P, Pasparakis M, Bleich M, Weinberg JM, Reichel CA, Bräsen JH, Kunzendorf U, Anders HJ, Stockwell BR, Green DR, Krautwald S | title = Synchronized renal tubular cell death involves ferroptosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 47 | pages = 16836–16841 | date = November 2014 | pmid = 25385600 | pmc = 4250130 | doi = 10.1073/pnas.1415518111 | doi-access = free | bibcode = 2014PNAS..11116836L }}{{cite journal | vauthors = Tonnus W, Meyer C, Steinebach C, Belavgeni A, von Mässenhausen A, Gonzalez NZ, Maremonti F, Gembardt F, Himmerkus N, Latk M, Locke S, Marschner J, Li W, Short S, Doll S, Ingold I, Proneth B, Daniel C, Kabgani N, Kramann R, Motika S, Hergenrother PJ, Bornstein SR, Hugo C, Becker JU, Amann K, Anders HJ, Kreisel D, Pratt D, Gütschow M, Conrad M, Linkermann A | title = Dysfunction of the key ferroptosis-surveilling systems hypersensitizes mice to tubular necrosis during acute kidney injury | journal = Nature Communications | volume = 12 | issue = 1 | pages = 4402 | date = July 2021 | pmid = 34285231 | pmc = 8292346 | doi = 10.1038/s41467-021-24712-6 | bibcode = 2021NatCo..12.4402T }}{{cite journal | vauthors = Wang Y, Zhang M, Bi R, Su Y, Quan F, Lin Y, Yue C, Cui X, Zhao Q, Liu S, Yang Y, Zhang D, Cao Q, Gao X | title = ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury | journal = Redox Biology | volume = 51 | pages = 102262 | date = May 2022 | pmid = 35180475 | pmc = 8857079 | doi = 10.1016/j.redox.2022.102262 }} 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.

During chemotherapy treatment, ferroptosis contributes to acute kidney injury.{{cite journal | vauthors = Tadokoro T, Ikeda M, Ide T, Deguchi H, Ikeda S, Okabe K, Ishikita A, Matsushima S, Koumura T, Yamada KI, Imai H, Tsutsui H | title = Mitochondria-dependent ferroptosis plays a pivotal role in doxorubicin cardiotoxicity | journal = JCI Insight | volume = 5 | issue = 9 | pages = e132747, 132747 | date = May 2020 | pmid = 32376803 | pmc = 7253028 | doi = 10.1172/jci.insight.132747 }}{{cite journal | vauthors = Mishima E, Sato E, Ito J, Yamada KI, Suzuki C, Oikawa Y, Matsuhashi T, Kikuchi K, Toyohara T, Suzuki T, Ito S, Nakagawa K, Abe T | title = Drugs Repurposed as Antiferroptosis Agents Suppress Organ Damage, Including AKI, by Functioning as Lipid Peroxyl Radical Scavengers | journal = Journal of the American Society of Nephrology | volume = 31 | issue = 2 | pages = 280–296 | date = February 2020 | pmid = 31767624 | pmc = 7003311 | doi = 10.1681/ASN.2019060570 }}{{cite journal | vauthors = Ikeda Y, Hamano H, Horinouchi Y, Miyamoto L, Hirayama T, Nagasawa H, Tamaki T, Tsuchiya K | title = Role of ferroptosis in cisplatin-induced acute nephrotoxicity in mice | journal = Journal of Trace Elements in Medicine and Biology | volume = 67 | pages = 126798 | date = September 2021 | pmid = 34087581 | doi = 10.1016/j.jtemb.2021.126798 | bibcode = 2021JTEMB..6726798I }} Reagents to image ferroptosis have been developed to monitor anticancer drug-induced acute kidney injury in mouse models.{{cite journal | vauthors = Zeng F, Nijiati S, Liu Y, Yang Q, Liu X, Zhang Q, Chen S, Su A, Xiong H, Shi C, Cai C, Lin Z, Chen X, Zhou Z | title = Ferroptosis MRI for early detection of anticancer drug-induced acute cardiac/kidney injuries | journal = Science Advances | volume = 9 | issue = 10 | pages = eadd8539 | date = March 2023 | pmid = 36888714 | pmc = 9995079 | doi = 10.1126/sciadv.add8539 | bibcode = 2023SciA....9D8539Z }}

Ferroptosis has been implicated in many immune processes including both adaptive and innate immunity and diseases such as infection and autoimmune disease.{{cite journal | vauthors = Wang P, Lu YQ | title = Ferroptosis: A Critical Moderator in the Life Cycle of Immune Cells | journal = Frontiers in Immunology | volume = 13 | pages = 877634 | date = 2022-05-10 | pmid = 35619718 | pmc = 9127082 | doi = 10.3389/fimmu.2022.877634 | doi-access = free }}{{cite journal | vauthors = Chen X, Kang R, Kroemer G, Tang D | title = Ferroptosis in infection, inflammation, and immunity | journal = The Journal of Experimental Medicine | volume = 218 | issue = 6 | pages = e20210518 | date = June 2021 | pmid = 33978684 | pmc = 8126980 | doi = 10.1084/jem.20210518 }}

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease.{{cite journal | vauthors = Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, Ruiz-Irastorza G, Hughes G | title = Systemic lupus erythematosus | journal = Nature Reviews. Disease Primers | volume = 2 | issue = 1 | pages = 16039 | date = June 2016 | pmid = 27306639 | doi = 10.1038/nrdp.2016.39 }} Studies have implicated a role for neutrophil death (NETosis) in SLE.{{cite journal | vauthors = Lande R, Ganguly D, Facchinetti V, Frasca L, Conrad C, Gregorio J, Meller S, Chamilos G, Sebasigari R, Riccieri V, Bassett R, Amuro H, Fukuhara S, Ito T, Liu YJ, Gilliet M | title = Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus | journal = Science Translational Medicine | volume = 3 | issue = 73 | pages = 73ra19 | date = March 2011 | pmid = 21389263 | pmc = 3399524 | doi = 10.1126/scitranslmed.3001180 }}{{cite journal | vauthors = Garcia-Romo GS, Caielli S, Vega B, Connolly J, Allantaz F, Xu Z, Punaro M, Baisch J, Guiducci C, Coffman RL, Barrat FJ, Banchereau J, Pascual V | title = Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus | journal = Science Translational Medicine | volume = 3 | issue = 73 | pages = 73ra20 | date = March 2011 | pmid = 21389264 | pmc = 3143837 | doi = 10.1126/scitranslmed.3001201 }}{{cite journal | vauthors = Lood C, Blanco LP, Purmalek MM, Carmona-Rivera C, De Ravin SS, Smith CK, Malech HL, Ledbetter JA, Elkon KB, Kaplan MJ | title = Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease | journal = Nature Medicine | volume = 22 | issue = 2 | pages = 146–153 | date = February 2016 | pmid = 26779811 | pmc = 4742415 | doi = 10.1038/nm.4027 }} Neutrophil ferroptosis is prevalent in patients with SLE and is induced by autoantibodies and interferon-alpha (IFN-α), which suppress GPX4 expression via the transcriptional repressor CREMα. Inhibition of ferroptosis was able to ameliorate SLE disease progression in the MRL/lpr mouse model of SLE.{{cite journal | vauthors = Li P, Jiang M, Li K, Li H, Zhou Y, Xiao X, Xu Y, Krishfield S, Lipsky PE, Tsokos GC, Zhang X | title = Glutathione peroxidase 4-regulated neutrophil ferroptosis induces systemic autoimmunity | journal = Nature Immunology | volume = 22 | issue = 9 | pages = 1107–1117 | date = September 2021 | pmid = 34385713 | pmc = 8609402 | doi = 10.1038/s41590-021-00993-3 }}

There is a genetic association between GPX4 and Crohn's disease.{{cite journal | vauthors = Jostins L, Ripke S, Weersma RK, Duerr RH, McGovern DP, Hui KY, Lee JC, Schumm LP, Sharma Y, Anderson CA, Essers J, Mitrovic M, Ning K, Cleynen I, Theatre E, Spain SL, Raychaudhuri S, Goyette P, Wei Z, Abraham C, Achkar JP, Ahmad T, Amininejad L, Ananthakrishnan AN, Andersen V, Andrews JM, Baidoo L, Balschun T, Bampton PA, Bitton A, Boucher G, Brand S, Büning C, Cohain A, Cichon S, D'Amato M, De Jong D, Devaney KL, Dubinsky M, Edwards C, Ellinghaus D, Ferguson LR, Franchimont D, Fransen K, Gearry R, Georges M, Gieger C, Glas J, Haritunians T, Hart A, Hawkey C, Hedl M, Hu X, Karlsen TH, Kupcinskas L, Kugathasan S, Latiano A, Laukens D, Lawrance IC, Lees CW, Louis E, Mahy G, Mansfield J, Morgan AR, Mowat C, Newman W, Palmieri O, Ponsioen CY, Potocnik U, Prescott NJ, Regueiro M, Rotter JI, Russell RK, Sanderson JD, Sans M, Satsangi J, Schreiber S, Simms LA, Sventoraityte J, Targan SR, Taylor KD, Tremelling M, Verspaget HW, De Vos M, Wijmenga C, Wilson DC, Winkelmann J, Xavier RJ, Zeissig S, Zhang B, Zhang CK, Zhao H, Silverberg MS, Annese V, Hakonarson H, Brant SR, Radford-Smith G, Mathew CG, Rioux JD, Schadt EE, Daly MJ, Franke A, Parkes M, Vermeire S, Barrett JC, Cho JH | title = Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease | journal = Nature | volume = 491 | issue = 7422 | pages = 119–124 | date = November 2012 | pmid = 23128233 | pmc = 3491803 | doi = 10.1038/nature11582 | bibcode = 2012Natur.491..119. }} Subsequent study found that small intestinal epithelial cells (IECs) from Crohn's disease patient samples show reduced GPX4 expression and activity and lipid peroxidation.{{cite journal | vauthors = Mayr L, Grabherr F, Schwärzler J, Reitmeier I, Sommer F, Gehmacher T, Niederreiter L, He GW, Ruder B, Kunz KT, Tymoszuk P, Hilbe R, Haschka D, Feistritzer C, Gerner RR, Enrich B, Przysiecki N, Seifert M, Keller MA, Oberhuber G, Sprung S, Ran Q, Koch R, Effenberger M, Tancevski I, Zoller H, Moschen AR, Weiss G, Becker C, Rosenstiel P, Kaser A, Tilg H, Adolph TE | title = Dietary lipids fuel GPX4-restricted enteritis resembling Crohn's disease | journal = Nature Communications | volume = 11 | issue = 1 | pages = 1775 | date = April 2020 | pmid = 32286299 | pmc = 7156516 | doi = 10.1038/s41467-020-15646-6 | bibcode = 2020NatCo..11.1775M }} The same study found that dietary lipids in Western diets such as the PUFA arachidonic acid can trigger enteritis resembling Crohn's disease in a mouse model.

File:Ferroptosis inducer structures.png

Many compounds commonly used in ferroptosis studies including erastin, RSL3 (RAS-selective lethal), ML162, and ML210 [from National Institutes of Health-Molecular Libraries Small Molecule Repository (NIH-MLSMR)] {{cite journal | vauthors = Weïwer M, Bittker JA, Lewis TA, Shimada K, Yang WS, MacPherson L, Dandapani S, Palmer M, Stockwell BR, Schreiber SL, Munoz B | title = Development of small-molecule probes that selectively kill cells induced to express mutant RAS | journal = Bioorganic & Medicinal Chemistry Letters | volume = 22 | issue = 4 | pages = 1822–1826 | date = February 2012 | pmid = 22297109 | pmc = 3528973 | doi = 10.1016/j.bmcl.2011.09.047 }} were initially identified in screens for compounds that can selectively kill cancerous mutant RAS cells.

Initial studies characterized the mitochondrial VDAC2 and VDAC3 as the targets of erastin, though it was later found that the mechanistic target of erastin is the cystine/glutamate transporter system x_c⁻. Erastin inhibits system x_c⁻, lowering intracellular GSH levels. Consequently, the GSH-dependent GPX4 is unable to detoxify lipid hydroperoxide species, leading to ferroptotic cell death. Derivatives of erastin have been prepared to improve aqueous solubility, potency, and metabolic stability, with imidazole ketone erastin (IKE) being the most extensively studied.{{cite journal | vauthors = Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, Cheah JH, Clemons PA, Shamji AF, Clish CB, Brown LM, Girotti AW, Cornish VW, Schreiber SL, Stockwell BR | title = Regulation of ferroptotic cancer cell death by GPX4 | journal = Cell | volume = 156 | issue = 1–2 | pages = 317–331 | date = January 2014 | pmid = 24439385 | pmc = 4076414 | doi = 10.1016/j.cell.2013.12.010 }}{{cite journal | vauthors = Larraufie MH, Yang WS, Jiang E, Thomas AG, Slusher BS, Stockwell BR | title = Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility | journal = Bioorganic & Medicinal Chemistry Letters | volume = 25 | issue = 21 | pages = 4787–4792 | date = November 2015 | pmid = 26231156 | pmc = 4653046 | doi = 10.1016/j.bmcl.2015.07.018 }}{{cite journal | vauthors = Zhang Y, Tan H, Daniels JD, Zandkarimi F, Liu H, Brown LM, Uchida K, O'Connor OA, Stockwell BR | title = Imidazole Ketone Erastin Induces Ferroptosis and Slows Tumor Growth in a Mouse Lymphoma Model | language = English | journal = Cell Chemical Biology | volume = 26 | issue = 5 | pages = 623–633.e9 | date = May 2019 | pmid = 30799221 | pmc = 6525071 | doi = 10.1016/j.chembiol.2019.01.008 }}

RSL3 and ML162 contain chloroacetamide moieties that can covalently react with nucleophilic residues. RSL3 and ML162 are able to bind to and inhibit GPX4 enzymatic activity or degrade GPX4 in lysate-based assays,{{cite journal | vauthors = Liu H, Forouhar F, Lin AJ, Wang Q, Polychronidou V, Soni RK, Xia X, Stockwell BR | title = Small-molecule allosteric inhibitors of GPX4 | journal = Cell Chemical Biology | volume = 29 | issue = 12 | pages = 1680–1693.e9 | date = December 2022 | pmid = 36423641 | pmc = 9772252 | doi = 10.1016/j.chembiol.2022.11.003 }} though it has been found that RSL3 and ML162 do not inhibit purified GPX4 in vitro and target other selenoproteins such as thioredoxin reductase 1 (TXNRD1).{{cite journal | vauthors = Cheff DM, Huang C, Scholzen KC, Gencheva R, Ronzetti MH, Cheng Q, Hall MD, Arnér ES | title = The ferroptosis inducing compounds RSL3 and ML162 are not direct inhibitors of GPX4 but of TXNRD1 | journal = Redox Biology | volume = 62 | pages = 102703 | date = June 2023 | pmid = 37087975 | pmc = 10149367 | doi = 10.1016/j.redox.2023.102703 }} However, other TXNRD1 inhibitors do not trigger ferroptosis, suggesting that TXNRD1 inhibition is not sufficient to trigger ferroptosis. The GPX4-inhibiting activity of RSL3 has also been suggested to be regulated by other factors such as 14-3-3ε{{cite journal | vauthors = Vučković AM, Bosello Travain V, Bordin L, Cozza G, Miotto G, Rossetto M, Toppo S, Venerando R, Zaccarin M, Maiorino M, Ursini F, Roveri A | title = Inactivation of the glutathione peroxidase GPx4 by the ferroptosis-inducing molecule RSL3 requires the adaptor protein 14-3-3ε | journal = FEBS Letters | volume = 594 | issue = 4 | pages = 611–624 | date = February 2020 | pmid = 31581313 | doi = 10.1002/1873-3468.13631 | hdl-access = free | hdl = 11577/3310112 }} or through broad targeting of the selenoproteome.{{cite journal | vauthors = DeAngelo SL, Zhao L, Dziechciarz S, Shin M, Solanki S, Balia A, El-Derany MO, Castillo C, Qin Y, Das NK, Bell HN, Paulo JA, Zhang Y, Rossiter NJ, McCulla EC, He J, Talukder I, Ng BW, Schafer ZT, Neamati N, Mancias JD, Koutmos M, Shah YM | title = Recharacterization of RSL3 reveals that the selenoproteome is a druggable target in colorectal cancer | journal = bioRxiv | pages = 2024.03.29.587381 | date = August 2024 | pmid = 38617233 | pmc = 11014488 | doi = 10.1101/2024.03.29.587381 }}

ML210 contains a nitroisoxazole group that acts as a masked nitrile-oxide electrophile. Specifically, in cellular and lysate contexts, ML210 undergoes ring-opening hydrolysis followed by a retro-Claisen-like condensation and ring-closing hydration to yield an unstable furoxan. Through a ring-opening tautomerization, this furoxan then yields a nitrile oxide that selectively reacts with selenocysteine residue 46 of GPX4.{{cite journal | vauthors = Eaton JK, Furst L, Ruberto RA, Moosmayer D, Hilpmann A, Ryan MJ, Zimmermann K, Cai LL, Niehues M, Badock V, Kramm A, Chen S, Hillig RC, Clemons PA, Gradl S, Montagnon C, Lazarski KE, Christian S, Bajrami B, Neuhaus R, Eheim AL, Viswanathan VS, Schreiber SL | title = Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles | journal = Nature Chemical Biology | volume = 16 | issue = 5 | pages = 497–506 | date = May 2020 | pmid = 32231343 | pmc = 7251976 | doi = 10.1038/s41589-020-0501-5 }}

File:ML210 mechanism.png

File:GCL inhibitors.png

Upstream of GPX4, depletion of GSH by inhibiting GSH biosynthesis also induces ferroptosis. Work from Kojin Therapeutics and Ono Pharmaceutical has demonstrated that inhibition of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in GSH biosynthesis, induces ferroptosis in cancer cell lines.{{Cite patent|number=WO2023085367A1|title=Gcl inhibitor|gdate=2023-05-19|invent1=岡田|invent2=梅村|invent3=犬飼|invent4=川俣|inventor1-first=拓也|inventor2-first=周平|inventor3-first=隆之|inventor4-first=貴裕|url=https://patents.google.com/patent/WO2023085367A1/en}} GCL also suppresses ferroptosis through a GSH-independent mechanisms such as limiting glutamate accumulation.{{Cite journal |last1=Kang |first1=Yun Pyo |last2=Mockabee-Macias |first2=Andrea |last3=Jiang |first3=Chang |last4=Falzone |first4=Aimee |last5=Prieto-Farigua |first5=Nicolas |last6=Stone |first6=Everett |last7=Harris |first7=Isaac S. |last8=DeNicola |first8=Gina M. |date=2020-12-22 |title=Non-canonical glutamate-cysteine ligase activity protects against ferroptosis |journal=Cell Metabolism |language=en |volume=33 |issue=1 |pages=174–189.e7 |doi=10.1016/j.cmet.2020.12.007 |pmc=7839835 |pmid=33357455}} Buthionine sulfoximine (BSO) has been commonly used as a tool compound to inhibit GCL, though BSO is relatively low potency. Accordingly, analogues have been reported that show improved potency and pharmacological properties that may be used in in vivo studies.File:FSP1 inhibitor structures.png

FSP1 inhibition is generally not sufficient to induce ferroptosis but FSP1 inhibitors such as iFSP1 (targeting the CoQ₁₀ binding site) and viFSP1 (versatile inhibitor of FSP1; targeting the NAD(P)H binding pocket) have been explored as ferroptosis sensitizers.{{cite journal | vauthors = Hendricks JM, Doubravsky CE, Wehri E, Li Z, Roberts MA, Deol KK, Lange M, Lasheras-Otero I, Momper JD, Dixon SJ, Bersuker K, Schaletzky J, Olzmann JA | title = Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis | journal = Cell Chemical Biology | volume = 30 | issue = 9 | pages = 1090–1103.e7 | date = September 2023 | pmid = 37178691 | pmc = 10524360 | doi = 10.1016/j.chembiol.2023.04.007 }}{{cite journal | vauthors = Nakamura T, Mishima E, Yamada N, Mourão AS, Trümbach D, Doll S, Wanninger J, Lytton E, Sennhenn P, Nishida Xavier da Silva T, Angeli JP, Sattler M, Proneth B, Conrad M | title = Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation | journal = Nature Structural & Molecular Biology | volume = 30 | issue = 11 | pages = 1806–1815 | date = November 2023 | pmid = 37957306 | pmc = 10643123 | doi = 10.1038/s41594-023-01136-y }}{{cite journal | vauthors = Yoshioka H, Kawamura T, Muroi M, Kondoh Y, Honda K, Kawatani M, Aono H, Waldmann H, Watanabe N, Osada H | title = Identification of a Small Molecule That Enhances Ferroptosis via Inhibition of Ferroptosis Suppressor Protein 1 (FSP1) | journal = ACS Chemical Biology | volume = 17 | issue = 2 | pages = 483–491 | date = February 2022 | pmid = 35128925 | doi = 10.1021/acschembio.2c00028 }} iFSP1 is not usable in rodent models, though viFSP1 is species-independent. FSEN1 is an uncompetitive inhibitor of FSP1 that binds to the FSP1–NADH–CoQ complex. 3-Phenylquinazolines (represented by icFSP1) do not competitively inhibit FSP1 enzymatic activity but rather trigger phase separation of FSP1 followed by induction of ferroptosis.{{cite journal | vauthors = Nakamura T, Hipp C, Santos Dias Mourão A, Borggräfe J, Aldrovandi M, Henkelmann B, Wanninger J, Mishima E, Lytton E, Emler D, Proneth B, Sattler M, Conrad M | title = Phase separation of FSP1 promotes ferroptosis | journal = Nature | volume = 619 | issue = 7969 | pages = 371–377 | date = July 2023 | pmid = 37380771 | pmc = 10338336 | doi = 10.1038/s41586-023-06255-6 | bibcode = 2023Natur.619..371N }} Notably, FSP1 activity can compensate for GPX4 loss and suppress ferroptosis in certain contexts.

Ferroptosis can be inhibited by lipophilic radical trapping antioxidants such as ferrostatin-1, liproxstatin-1, and vitamin E. Chelation of iron by agents such as desferrioxamine mesylate (DFO) also prevents lipid peroxidation and suppresses ferroptosis.{{cite journal | vauthors = Zhu H, Cen J, Hong C, Wang H, Wen Y, He Q, Yu Y, Cao J, Chen W | title = Targeting Labile Iron-Mediated Ferroptosis Provides a Potential Therapeutic Strategy for Rhabdomyolysis-Induced Acute Kidney Injury | journal = ACS Chemical Biology | volume = 18 | issue = 6 | pages = 1294–1304 | date = June 2023 | pmid = 37172039 | doi = 10.1021/acschembio.2c00914 }}

• Cystine/glutamate transporter (SLC7A11)
• Erastin
• Glutathione peroxidase 4 (GPX4)
• XJB-5-131

{{Reflist}}

• [http://www.genome.jp/dbget-bin/www_bget?hsa04216 KEGG pathway entry]

Category:Programmed cell death

Category:Medical aspects of death

Category:Cellular processes