Lipoxygenase in Ferroptosis

  • Xiaoyuan Mao


Cell death is indispensable for the maintenance of organic homeostasis and embryonic development under physical circumstances. Ferroptosis is a newly discovered type of cell death by Stockwell research group in 2012. It is distinct from other cell death modalities including apoptosis, necroptosis, autophagy, and pyroptosis at morphological, genetic, and biochemical levels. It is well known that ferroptotic cell death occurs through lipid peroxidation accumulation. Lipoxygenase (ALOX) serves as one of the major enzymes for the oxygenation of arachidonic acid (AA), an essential polyunsaturated fatty acid (PUFA), finally triggering lipid peroxidation and ferroptosis. Here, we make a summarization of basic knowledge of ALOX including its nomenclature, distribution in different organs, and its metabolites. Additionally, the relationship between ALOX and ferroptosis in human diseases such as neurological disorders and cancers is also discussed. We propose that ALOX may serve as a potential therapeutic target for treating multiple disorders via suppressing ferroptosis.


Cell death Ferroptosis Lipoxygenase Lipid peroxidation Therapeutic target 



Arachidonic acid


Acyl-CoA synthetase long chain family member 4


Alzheimer’s disease


Adrenic acid




Docosahexaenoic acid


Eicosapentaenoic acid




Glutathione peroxidase 4


Hydroxyeicosatetraenoic acid


Hydroperoxyeicosatetraenoic acid


Hydroperoxyoctadecadienoic acid


Hydroxyoctadecadienoic acid


Linoleic acid






PE-binding protein 1


Polyunsaturated fatty acids


Reactive oxygen species


  1. Abeti R, Parkinson MH, Hargreaves IP et al (2016) Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich’s ataxia. Cell Death Dis 7:e2237PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ackermann JA, Hofheinz K, Zaiss MM et al (2017) The double-edged role of 12/15-lipoxygenase during inflammation and immunity. Biochim Biophys Acta Mol Cell Biol Lipids 1862(4):371–381PubMedCrossRefGoogle Scholar
  3. Ai F, Zheng J, Zhang Y et al (2017) Inhibition of 12/15-LO ameliorates CVB3-induced myocarditis by activating Nrf2. Chem Biol Interact 272:65–71PubMedCrossRefGoogle Scholar
  4. Chu J, Pratico D (2016) The 5-Lipoxygenase as modulator of Alzheimer’s gamma-secretase and therapeutic target. Brain Res Bull 126(Pt 2):207–212PubMedPubMedCentralCrossRefGoogle Scholar
  5. Conrad M, Angeli JP, Vandenabeele P et al (2016) Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov 15(5):348–366PubMedPubMedCentralCrossRefGoogle Scholar
  6. Conrad M, Kagan VE, Bayir H et al (2018) Regulation of lipid peroxidation and ferroptosis in diverse species. Genes Dev 32(9-10):602–619PubMedPubMedCentralCrossRefGoogle Scholar
  7. Cyrus T, Pratico D, Zhao L et al (2001) Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e-deficient mice. Circulation 103(18):2277–2282PubMedCrossRefGoogle Scholar
  8. Deas E, Cremades N, Angelova PR et al (2016) Alpha-synuclein oligomers interact with metal ions to induce oxidative stress and neuronal death in Parkinson’s disease. Antioxid Redox Signal 24(7):376–391PubMedPubMedCentralCrossRefGoogle Scholar
  9. Dixon SJ, Lemberg KM, Lamprecht MR et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072PubMedPubMedCentralCrossRefGoogle Scholar
  10. Dobrian AD, Lieb DC, Cole BK et al (2011) Functional and pathological roles of the 12- and 15-lipoxygenases. Prog Lipid Res 50(1):115–131PubMedCrossRefGoogle Scholar
  11. Doll S, Proneth B, Tyurina YY et al (2017) ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 13(1):91–98CrossRefGoogle Scholar
  12. Dolma S, Lessnick SL, Hahn WC et al (2003) Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3(3):285–296CrossRefGoogle Scholar
  13. Drefs M, Thomas MN, Guba M et al (2017) Modulation of glutathione hemostasis by inhibition of 12/15-lipoxygenase prevents ROS-mediated cell death after hepatic ischemia and reperfusion. Oxidative Med Cell Longev 2017:8325754CrossRefGoogle Scholar
  14. Elshazly SM, Abd El Motteleb DM, Nassar NN (2013) The selective 5-LOX inhibitor 11-keto-beta-boswellic acid protects against myocardial ischemia reperfusion injury in rats: involvement of redox and inflammatory cascades. Naunyn Schmiedeberg’s Arch Pharmacol 386(9):823–833CrossRefGoogle Scholar
  15. Friedmann Angeli JP, Schneider M, Proneth B et al (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16(12):1180–1191CrossRefGoogle Scholar
  16. Garg AD, Agostinis P (2017) Cell death and immunity in cancer: from danger signals to mimicry of pathogen defense responses. Immunol Rev 280(1):126–148PubMedCrossRefGoogle Scholar
  17. Hangauer MJ, Viswanathan VS, Ryan MJ et al (2017) Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551(7679):247–250PubMedPubMedCentralCrossRefGoogle Scholar
  18. Heirman I, Ginneberge D, Brigelius-Flohe R et al (2006) Blocking tumor cell eicosanoid synthesis by GP x 4 impedes tumor growth and malignancy. Free Radic Biol Med 40(2):285–294PubMedCrossRefGoogle Scholar
  19. Imai H, Matsuoka M, Kumagai T et al (2017) Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis. Curr Top Microbiol Immunol 403:143–170Google Scholar
  20. Joshi YB, Giannopoulos PF, Pratico D (2015) The 12/15-lipoxygenase as an emerging therapeutic target for Alzheimer’s disease. Trends Pharmacol Sci 36(3):181–186PubMedPubMedCentralCrossRefGoogle Scholar
  21. Kagan VE, Mao G, Qu F et al (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13(1):81–90CrossRefGoogle Scholar
  22. Karuppagounder SS, Alin L, Chen Y et al (2018) N-acetylcysteine targets 5 lipoxygenase-derived, toxic lipids and can synergize with prostaglandin E2 to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice. Ann Neurol 84(6):854–872PubMedPubMedCentralCrossRefGoogle Scholar
  23. Kenny EM, Fidan E, Yang Q et al (2019) Ferroptosis contributes to neuronal death and functional outcome after traumatic brain injury. Crit Care Med 47(3):410–418PubMedCrossRefGoogle Scholar
  24. Khor TO, Huang MT, Prawan A et al (2008) Increased susceptibility of Nrf2 knockout mice to colitis-associated colorectal cancer. Cancer Prev Res (Phila) 1(3):187–191CrossRefGoogle Scholar
  25. Krieg P, Furstenberger G (2014) The role of lipoxygenases in epidermis. Biochim Biophys Acta 1841(3):390–400PubMedCrossRefGoogle Scholar
  26. Kroemer G, Galluzzi L, Vandenabeele P et al (2009) Classification of cell death: recommendations of the Nomenclature Committee on Cell Death 2009. Cell Death Differ 16(1):3–11PubMedCrossRefGoogle Scholar
  27. Kuhn H, Borchert A (2002) Regulation of enzymatic lipid peroxidation: the interplay of peroxidizing and peroxide reducing enzymes. Free Radic Biol Med 33(2):154–172PubMedCrossRefGoogle Scholar
  28. Li QQ, Li Q, Jia JN et al (2018) 12/15 lipoxygenase: a crucial enzyme in diverse types of cell death. Neurochem Int 118:34–41PubMedCrossRefGoogle Scholar
  29. Li Y, Chen Q, Ran D et al (2019a) Changes in the levels of 12/15-lipoxygenase, apoptosis-related proteins and inflammatory factors in the cortex of diabetic rats and the neuroprotection of baicalein. Free Radic Biol Med 134:239–247PubMedCrossRefGoogle Scholar
  30. Li Q, Li Q-Q, Jia J-N, Sun Q-Y, Zhou H-H, Jin W-L, Mao X-Y (2019b) Baicalein exerts neuroprotective effects in FeCl3-induced posttraumatic epileptic seizures via suppressing ferroptosis. Front Pharmacol 10(638):1–13Google Scholar
  31. Liu Y, Wang W, Li Y et al (2015) The 5-lipoxygenase inhibitor zileuton confers neuroprotection against glutamate oxidative damage by inhibiting ferroptosis. Biol Pharm Bull 38(8):1234–1239CrossRefGoogle Scholar
  32. Maloberti PM, Duarte AB, Orlando UD et al (2010) Functional interaction between acyl-CoA synthetase 4, lipooxygenases and cyclooxygenase-2 in the aggressive phenotype of breast cancer cells. PLoS One 5(11):e15540PubMedPubMedCentralCrossRefGoogle Scholar
  33. Manev H, Uz T, Sugaya K et al (2000) Putative role of neuronal 5-lipoxygenase in an aging brain. FASEB J 14(10):1464–1469PubMedCrossRefGoogle Scholar
  34. Mashima R, Okuyama T (2015) The role of lipoxygenases in pathophysiology; new insights and future perspectives. Redox Biol 6:297–310PubMedPubMedCentralCrossRefGoogle Scholar
  35. Muller T, Dewitz C, Schmitz J et al (2017) Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell Mol Life Sci 74(19):3631–3645PubMedPubMedCentralCrossRefGoogle Scholar
  36. Orlando UD, Garona J, Ripoll GV et al (2012) The functional interaction between Acyl-CoA synthetase 4, 5-lipooxygenase and cyclooxygenase-2 controls tumor growth: a novel therapeutic target. PLoS One 7(7):e40794PubMedPubMedCentralCrossRefGoogle Scholar
  37. Paul BD, Sbodio JI, Xu R et al (2014) Cystathionine gamma-lyase deficiency mediates neurodegeneration in Huntington’s disease. Nature 509(7498):96–100PubMedPubMedCentralCrossRefGoogle Scholar
  38. Probst L, Dachert J, Schenk B et al (2017) Lipoxygenase inhibitors protect acute lymphoblastic leukemia cells from ferroptotic cell death. Biochem Pharmacol 140:41–52PubMedCrossRefGoogle Scholar
  39. Ribeiro AR, do Nascimento Valenca JD, da Silva Santos J et al (2016) The effects of baicalein on gastric mucosal ulcerations in mice: protective pathways and anti-secretory mechanisms. Chem Biol Interact 260:33–41PubMedCrossRefGoogle Scholar
  40. Roos J, Grosch S, Werz O et al (2016) Regulation of tumorigenic Wnt signaling by cyclooxygenase-2, 5-lipoxygenase and their pharmacological inhibitors: a basis for novel drugs targeting cancer cells? Pharmacol Ther 157:43–64PubMedCrossRefGoogle Scholar
  41. Schneider M, Wortmann M, Mandal PK et al (2010) Absence of glutathione peroxidase 4 affects tumor angiogenesis through increased 12/15-lipoxygenase activity. Neoplasia 12(3):254–263PubMedPubMedCentralCrossRefGoogle Scholar
  42. Shah R, Shchepinov MS, Pratt DA (2018) Resolving the role of lipoxygenases in the initiation and execution of ferroptosis. ACS Cent Sci 4(3):387–396PubMedPubMedCentralCrossRefGoogle Scholar
  43. Shintoku R, Takigawa Y, Yamada K et al (2017) Lipoxygenase-mediated generation of lipid peroxides enhances ferroptosis induced by erastin and RSL3. Cancer Sci 108(11):2187–2194PubMedPubMedCentralCrossRefGoogle Scholar
  44. Singh NK, Rao GN (2019) Emerging role of 12/15-Lipoxygenase (ALOX15) in human pathologies. Prog Lipid Res 73:28–45PubMedCrossRefGoogle Scholar
  45. Skouta R, Dixon SJ, Wang J et al (2014) Ferrostatins inhibit oxidative lipid damage and cell death in diverse disease models. J Am Chem Soc 136(12):4551–4556PubMedPubMedCentralCrossRefGoogle Scholar
  46. Stockwell BR, Friedmann Angeli JP, Bayir H et al (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171(2):273–285PubMedPubMedCentralCrossRefGoogle Scholar
  47. Vagnozzi AN, Giannopoulos PF, Pratico D (2018) Brain 5-lipoxygenase over-expression worsens memory, synaptic integrity, and tau pathology in the P301S mice. Aging Cell 17(1). PubMedCentralCrossRefPubMedGoogle Scholar
  48. Wang Y, Zhou K, Li T et al (2017a) Inhibition of autophagy prevents irradiation-induced neural stem and progenitor cell death in the juvenile mouse brain. Cell Death Dis 8(3):e2694PubMedPubMedCentralCrossRefGoogle Scholar
  49. Wang H, An P, Xie E et al (2017b) Characterization of ferroptosis in murine models of hemochromatosis. Hepatology 66(2):449–465PubMedPubMedCentralCrossRefGoogle Scholar
  50. Wenzel SE, Tyurina YY, Zhao J et al (2017) PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171(3):628–641.e626PubMedPubMedCentralCrossRefGoogle Scholar
  51. Wu X, Zhi F, Lun W et al (2018) Baicalin inhibits PDGF-BB-induced hepatic stellate cell proliferation, apoptosis, invasion, migration and activation via the miR-3595/ACSL4 axis. Int J Mol Med 41(4):1992–2002PubMedPubMedCentralGoogle Scholar
  52. Xie Y, Hou W, Song X et al (2016a) Ferroptosis: process and function. Cell Death Differ 23(3):369–379PubMedPubMedCentralCrossRefGoogle Scholar
  53. Xie Y, Song X, Sun X et al (2016b) Identification of baicalein as a ferroptosis inhibitor by natural product library screening. Biochem Biophys Res Commun 473(4):775–780CrossRefPubMedPubMedCentralGoogle Scholar
  54. Xie Y, Zhu S, Song X et al (2017) The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep 20(7):1692–1704CrossRefGoogle Scholar
  55. Yang WS, Kim KJ, Gaschler MM et al (2016) Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA 113(34):E4966–E4975CrossRefGoogle Scholar
  56. Yeh CH, Ma KH, Liu PS et al (2015) Baicalein decreases hydrogen peroxide-induced damage to NG108-15 cells via upregulation of Nrf2. J Cell Physiol 230(8):1840–1851PubMedCrossRefGoogle Scholar
  57. Yu H, Guo P, Xie X et al (2017) Ferroptosis, a new form of cell death, and its relationships with tumourous diseases. J Cell Mol Med 21(4):648–657PubMedPubMedCentralCrossRefGoogle Scholar
  58. Yuan H, Li X, Zhang X et al (2016) Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun 478(3):1338–1343CrossRefGoogle Scholar
  59. Zhang Y, Gao Z, Liu J et al (2011) Protective effects of baicalin and quercetin on an iron-overloaded mouse: comparison of liver, kidney and heart tissues. Nat Prod Res 25(12):1150–1160PubMedCrossRefGoogle Scholar
  60. Zhang Z, Cui W, Li G et al (2012) Baicalein protects against 6-OHDA-induced neurotoxicity through activation of Keap1/Nrf2/HO-1 and involving PKCalpha and PI3K/AKT signaling pathways. J Agric Food Chem 60(33):8171–8182PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Xiaoyuan Mao
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of Clinical Pharmacology, Xiangya HospitalCentral South UniversityChangshaP. R. China
  2. 2.Hunan Key Laboratory of Pharmacogenetics, Institute of Clinical PharmacologyCentral South UniversityChangshaP. R. China
  3. 3.Engineering Research Center of Applied Technology of Pharmacogenomics, Ministry of EducationChangshaP. R. China
  4. 4.National Clinical Research Center for Geriatric DisordersChangshaP. R. China

Personalised recommendations