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Targeting lipid metabolism for ferroptotic cancer therapy

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Abstract

It has been 10 years since the concept of ferroptosis was put forward and research focusing on ferroptosis has been increasing continuously. Ferroptosis is driven by iron-dependent lipid peroxidation, which can be antagonized by glutathione peroxidase 4 (GPX4), ferroptosis inhibitory protein 1 (FSP1), dihydroorotate dehydrogenase (DHODH) and Fas-associated factor 1 (FAF1). Various cellular metabolic events, including lipid metabolism, can modulate ferroptosis sensitivity. It is worth noting that the reprogramming of lipid metabolism in cancer cells can promote the occurrence and development of tumors. The metabolic flexibility of cancer cells opens the possibility for the coordinated targeting of multiple lipid metabolic pathways to trigger cancer cells ferroptosis. In addition, cancer cells must obtain immortality, escape from programmed cell death including ferroptosis, to promote cancer progression, which provides new perspectives for improving cancer therapy. Targeting the vulnerability of ferroptosis has received attention as one of the significant possible strategies to treat cancer given its role in regulating tumor cell survival. We review the impact of iron and lipid metabolism on ferroptosis and the potential role of the crosstalk of lipid metabolism reprogramming and ferroptosis in antitumor immunity and sum up agents targeting lipid metabolism and ferroptosis for cancer therapy.

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Abbreviations

GPX4:

Glutathione peroxidase 4

FSP1:

Ferroptosis inhibitory protein 1

DHODH:

Dihydroorotate dehydrogenase

FAF1:

Fas-associated factor 1

PUFAs:

Polyunsaturated fatty acids

ROS:

Reactive oxygen species

LIP:

Labile iron pool

LOXs:

Lipoxygenases

POR:

Cytochrome P450 oxidoreductase

CSCs:

Cancer stem cells

TF:

Transferrin

TFRC:

Transferrin receptor

CTCs:

Circulating tumor cells

DMT1:

Divalent metal transporter 1

NCOA4:

Nuclear receptor coactivator 4

GOT1:

Cytosolic aspartate aminotransaminase

HMOX1:

Heme oxygenase 1

NFS1:

Nitrogenfixation 1

PCBP2:

Poly rC binding-protein 2

AA:

Arachidonoyl

AdA:

Adrenoyl

ACSL4:

Acyl-CoA synthetase long-chain family member 4

PEs:

Phosphatidylethanolamines

MUFAs:

Monounsaturated fatty acids

POA:

Palmitic acid

OA:

Oleic acid

ACSL3:

Acyl-CoA synthetase long chain family member 3

SFA:

Saturated fatty acyl

PUFA ePLs:

Polyunsaturated ether phospholipids

LPCAT3:

Lysophosphatidylcholine acyltransferase 3

PKCβII:

Protein kinase C-βII isoform

PEBP1:

Phosphatidylethanolamine-binding protein 1

4-HNE:

4-Hydroxynonenal

MDA:

Malondialdehyde

CoQ10:

Coenzyme Q10

a-TOC:

Alpha-tocopherol

CoQ:

Ubiquinone

CoQH2:

Ubiquinol

Nrf2:

Nuclear factor erythroid 2-related factor 2

Sec:

Selenocysteine

TFH:

Follicular helper T cells

TFAP2C:

Transcription factor AP-2γ

SP1:

Specific protein 1

GSH:

Glutathione

GCL:

Glutamate-cysteineligase

BSO:

Butionine sulfoximine

GCLC:

Glutamic acid cysteine ligase catalytic subunit

BAP1:

BRCA1-associated protein 1

CSLCs:

Cancer stem cell-like cells

BCSCs:

Breast cancer stem cells

CAFs:

Cancer-associated fibroblasts

MESH1:

Metazoan SpoT Homolog 1

ER:

Endoplasmic reticulum

AIFM2:

Apoptosis-inducing factor mitochondria-associated 2

AIF:

Apoptosis inducing factor

NDH-2:

Type 2 NADH ubiquinone oxidoreductase

IPP:

Isopentenyl pyrophosphate

BH4:

Tetrahydrobiopterin

DHFR:

Dihydrofolate reductase

BH2:

Dihydrobiopterin

GCH1:

GTP-dependent cyclohydrolase 1

iPLA2β:

Calcium-independent phospholipase A2β

27HC:

27-Hydroxycholesterol

SQS:

Squalene synthase

SQLE:

Squalene monooxygenase

ACSF2:

Acyl-CoA synthetase family member 2

CS:

Citrate synthase

SCD1:

Stearoyl-CoA desaturase 1

FADS2:

Acyl-CoA 6 desaturase

CSCs:

Cancer stem cells

SREBPs:

Sterol regulatory element binding proteins

BCAT2:

Branched-chain amino acid aminotransferase 2

AMPK:

AMP-activated protein kinase

LKB1:

Liver kinase B1

FAT:

Fatty acid translocase

LDs:

Lipid droplets

DGATi:

Diacylglycerol acyltransferase inhibitor

TPD52:

Tumor protein D52

HILPDA:

Hypoxia inducible lipid droplet-associated

DAMPs:

Damage associated molecular patterns

VLDLRs:

Very low-density lipoproteins

LDLRs:

LDL receptors

LSRs:

Ipolysis-stimulating receptors

ACLY:

ATP-citrate lyase

ACSS2:

Acyl-CoA synthetase short chain family member 2

ACC:

Acetyl-CoA carboxylase

USP22:

Ubiquitin-specific enzyme 22

FADS:

FA desaturase

ELOVL:

Elongating very long-chain fatty acid enzyme

GCs:

Gastric cancer cells

HMGCRs:

HMG-CoA reductases

SQLE:

Squalene epoxidase

ALCLs:

Anaplastic large cell lymphomas

EMT:

Epithelial-mesenchymal transition

FAO:

Fatty acid oxidation

TAGs:

Triacylglycerols

CEs:

Cholesteryl esters

DGAT1:

Diacylglycerol-acyltransferase 1

MGL:

Monoacylglycerol lipase

ATGL:

Lipase fat triglyceride lipase

HSL:

Hormone-sensitive lipase

TME:

Tumor microenvironment

STAT3:

Transcription 3

ALOX15:

Arachidonic acid lipoxygenase 15

STAT1:

Transcription 1

PGE2:

Prostaglandin E2

cDC1:

Conventional type 1 dendritic cells

NK:

Natural killer

OXPLs:

Oxidized phospholipids

TLR2:

Toll-like receptor 2

iNOS:

Inducible nitric oxide synthase

MZ:

Marginal zone

ICD:

Immunogenic cell death

HMGB1:

High mobility histone B1

AGER:

Advanced glycosylation end-product specific receptor

PDT:

Photodynamic therapy

BMDCs:

Bone marrow-derived dendritic cells

TAMs:

Tumor associated macrophages

HCC:

Hepatocellular carcinoma

2D:

Two-dimensional

3D:

Three-dimensional

NSCLC:

Non-small cell lung cancer

BetA:

Betulinic acid

SCLC:

Small-cell lung cancer

HDLNPs:

HDL-like nanoparticle

SCARB1:

Scavenger receptor class B member 1

INSIG1:

Insulin induced gene 1

HMGCS1:

HMG-CoA synthase 1

IKE:

Imidazole-ketone-erastin

References

  1. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Stockwell BR, Angeli JPF, Bayir H, Bush AI, Conrad M, Dixon SJ et al (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171(2):273–285. https://doi.org/10.1016/j.cell.2017.09.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS et al (2014) Regulation of Ferroptotic Cancer Cell Death by GPX4. Cell 156(1–2):317–331. https://doi.org/10.1016/j.cell.2013.12.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold L et al (2019) FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575(7784):693. https://doi.org/10.1038/s41586-019-1707-0

    Article  CAS  PubMed  Google Scholar 

  5. Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH et al (2019) The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575(7784):688–692. https://doi.org/10.1038/s41586-019-1705-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mao C, Liu XG, Zhang YL, Lei G, Yan YL, Lee H al (2021) DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 593(7860):586–. https://doi.org/10.1038/s41586-021-03539-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cui S, Simmons G Jr, Vale G, Deng Y, Kim J, Kim H al (2022) FAF1 blocks ferroptosis by inhibiting peroxidation of polyunsaturated fatty acids. Proc Natl Acad Sci U S A 119(17):e2107189119. https://doi.org/10.1073/pnas.2107189119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Li J, Cao F, Yin HL, Huang ZJ, Lin ZT, Mao N, al, (2020) Ferroptosis: past, present and future. Cell Death Dis. https://doi.org/10.1038/s41419-020-2298-2

    Article  PubMed  PubMed Central  Google Scholar 

  9. Stine ZE, Schug ZT, Salvino JM, Dang CV (2022) Targeting cancer metabolism in the era of precision oncology. Nat Rev Drug Discovery 21(2):141–162. https://doi.org/10.1038/s41573-021-00339-6

    Article  CAS  PubMed  Google Scholar 

  10. Koundouros N, Poulogiannis G (2020) Reprogramming of fatty acid metabolism in cancer. Br J Cancer 122(1):4–22. https://doi.org/10.1038/s41416-019-0650-z

    Article  CAS  PubMed  Google Scholar 

  11. Zheng J, Conrad M (2020) The metabolic underpinnings of ferroptosis. Cell Metab 32(6):920–937. https://doi.org/10.1016/j.cmet.2020.10.011

    Article  CAS  PubMed  Google Scholar 

  12. Zou Y, Palte MJ, Deik AA, Li HX, Eaton JK, Wang WY et al (2019) A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun. https://doi.org/10.1038/s41467-019-09277-9

    Article  PubMed  PubMed Central  Google Scholar 

  13. Yang WS, Stockwell BR (2016) Ferroptosis: death by lipid peroxidation. Trends Cell Biol 26(3):165–176. https://doi.org/10.1016/j.tcb.2015.10.014

    Article  CAS  PubMed  Google Scholar 

  14. Hassannia B, Vandenabeele P, Vanden Berghe T (2019) Targeting ferroptosis to iron out cancer. Cancer Cell 35(6):830–849. https://doi.org/10.1016/j.ccell.2019.04.002

    Article  CAS  PubMed  Google Scholar 

  15. Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A al (2017) Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551(7679):247–250. https://doi.org/10.1038/nature24297

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Liao P, Wang W, Wang W, Kryczek I, Li X, Bian Y al (2022) CD8(+) T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell 40(4):365–378e366. https://doi.org/10.1016/j.ccell.2022.02.003

    Article  CAS  PubMed  Google Scholar 

  17. Chen X, Kang R, Kroemer G, Tang D (2021) Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol 18(5):280–296. https://doi.org/10.1038/s41571-020-00462-0

    Article  CAS  PubMed  Google Scholar 

  18. Liu Y, Duan C, Dai R, Zeng Y (2021) Ferroptosis-mediated crosstalk in the tumor microenvironment implicated in cancer progression and therapy. Front Cell Dev Biol 9:739392. https://doi.org/10.3389/fcell.2021.739392

    Article  PubMed  PubMed Central  Google Scholar 

  19. Winterbourn CC (1995) Toxicity of iron and hydrogen peroxide: the Fenton reaction. Toxicol Lett 82–83:969–974. https://doi.org/10.1016/0378-4274(95)03532-x

    Article  PubMed  Google Scholar 

  20. Torti SV, Manz DH, Paul BT, Blanchette-Farra N, Torti FM (2018) Iron and Cancer. Annu Rev Nutr 38:97–125. https://doi.org/10.1146/annurev-nutr-082117-051732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Doll S, Conrad M (2017) Iron and ferroptosis: a still ill-defined liaison. IUBMB Life 69(6):423–434. https://doi.org/10.1002/iub.1616

    Article  CAS  PubMed  Google Scholar 

  22. Rodriguez R, Schreiber SL, Conrad M (2022) Persister cancer cells: iron addiction and vulnerability to ferroptosis. Mol Cell 82(4):728–740. https://doi.org/10.1016/j.molcel.2021.12.001

    Article  CAS  PubMed  Google Scholar 

  23. Recalcati S, Gammella E, Cairo G (2019) Dysregulation of iron metabolism in cancer stem cells. Free Radic Biol Med 133:216–220. https://doi.org/10.1016/j.freeradbiomed.2018.07.015

    Article  CAS  PubMed  Google Scholar 

  24. Feng H, Schorpp K, Jin J, Yozwiak CE, Hoffstrom BG, Decker AM et al (2020) Transferrin Receptor Is a Specific Ferroptosis Marker. Cell Rep 30(10):3411. https://doi.org/10.1016/j.celrep.2020.02.049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hong X, Roh W, Sullivan RJ, Wong KHK, Wittner BS, Guo H et al (2021) The lipogenic regulator SREBP2 induces transferrin in circulating melanoma cells and suppresses ferroptosis. Cancer Discov 11(3):678–695. https://doi.org/10.1158/2159-8290.CD-19-1500

    Article  CAS  PubMed  Google Scholar 

  26. El Hout M, Dos Santos L, Hamai A, Mehrpour M (2018) A promising new approach to cancer therapy: targeting iron metabolism in cancer stem cells. Sem Cancer Biol 53:125–138. https://doi.org/10.1016/j.semcancer.2018.07.009

    Article  CAS  Google Scholar 

  27. Gao MH, Monian P, Pan QH, Zhang W, Xiang J, Jiang XJ (2016) Ferroptosis is an autophagic cell death process. Cell Res 26(9):1021–1032. https://doi.org/10.1038/cr.2016.95

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Torii S, Shintoku R, Kubota C, Yaegashi M, Torii R, Sasaki M al (2016) An essential role for functional lysosomes in ferroptosis of cancer cells. Biochem J 473:769–777. https://doi.org/10.1042/Bj20150658

    Article  CAS  PubMed  Google Scholar 

  29. Hou W, Xie YC, Song XX, Sun XF, Lotze MT, Zeh HJet al (2016) Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12(8):1425–1428. https://doi.org/10.1080/15548627.2016.1187366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rizzollo F, More S, Vangheluwe P, Agostinis P (2021) The lysosome as a master regulator of iron metabolism. Trends Biochem Sci 46(12):960–975. https://doi.org/10.1016/j.tibs.2021.07.003

    Article  CAS  PubMed  Google Scholar 

  31. Kremer DM, Nelson BS, Lin L, Yarosz EL, Halbrook CJ, Kerk SA et al (2021) GOT1 inhibition promotes pancreatic cancer cell death by ferroptosis. Nat Commun. https://doi.org/10.1038/s41467-021-24859-2

    Article  PubMed  PubMed Central  Google Scholar 

  32. Sun XF, Ou ZH, Chen RC, Niu XH, Chen D, Kang R al (2016) Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 63(1):173–184. https://doi.org/10.1002/hep.28251

    Article  CAS  PubMed  Google Scholar 

  33. Chang LC, Chiang SK, Chen SE, Yu YL, Chou RH, Chang WC (2018) Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis. Cancer Lett 416:124–137. https://doi.org/10.1016/j.canlet.2017.12.025

    Article  CAS  PubMed  Google Scholar 

  34. Alvarez SW, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S et al (2017) NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 551(7682):639–643. https://doi.org/10.1038/nature24637

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Brown CW, Amante JJ, Chhoy P, Elaimy AL, Liu HB, Zhu LJ et al (2019) Prominin2 drives ferroptosis resistance by stimulating iron export. Dev Cell 51(5):575. https://doi.org/10.1016/j.devcel.2019.10.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ganz T (2005) Cellular iron: ferroportin is the only way out. Cell Metab 1(3):155–157. https://doi.org/10.1016/j.cmet.2005.02.005

    Article  CAS  PubMed  Google Scholar 

  37. Drakesmith H, Nemeth E, Ganz T (2015) Ironing out ferroportin. Cell Metab 22(5):777–787. https://doi.org/10.1016/j.cmet.2015.09.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yang QY, Liu W, Zhang SP, Liu SJ (2020) The cardinal roles of ferroportin and its partners in controlling cellular iron in and out. Life Sci. https://doi.org/10.1016/j.lfs.2020.118135

    Article  PubMed  PubMed Central  Google Scholar 

  39. Tang Z, Jiang W, Mao M, Zhao J, Chen J, Cheng N (2021) Deubiquitinase USP35 modulates ferroptosis in lung cancer via targeting ferroportin. Clin Transl Med 11(4):e390. https://doi.org/10.1002/ctm2.390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li Y, Zeng X, Lu D, Yin M, Shan M, Gao Y (2021) Erastin induces ferroptosis via ferroportin-mediated iron accumulation in endometriosis. Hum Reprod 36(4):951–964. https://doi.org/10.1093/humrep/deaa363

    Article  CAS  PubMed  Google Scholar 

  41. Yanatori I, Richardson DR, Imada K, Kishi F (2016) Iron export through the transporter ferroportin 1 is modulated by the iron chaperone PCBP2. J Biol Chem 291(33):17303–17318. https://doi.org/10.1074/jbc.M116.721936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. De Bose-Boyd RA (2018) Significance and regulation of lipid metabolism. Semin Cell Dev Biol 81:97. https://doi.org/10.1016/j.semcdb.2017.12.003

    Article  Google Scholar 

  43. Beloribi-Djefaflia S, Vasseur S, Guillaumond F (2016) Lipid metabolic reprogramming in cancer cells. Oncogenesis 5:e189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Stockwell BR (2022) Ferroptosis turns 10: Emerging mechanisms, physiological functions, and therapeutic applications. Cell 185(14):2401–2421. https://doi.org/10.1016/j.cell.2022.06.003

    Article  CAS  PubMed  Google Scholar 

  45. Liang DG, Minikes AM, Jiang XJ (2022) Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell 82(12):2215–2227. https://doi.org/10.1016/j.molcel.2022.03.022

    Article  CAS  PubMed  Google Scholar 

  46. Lee JY, Kim WK, Bae KH, Lee SC, Lee EW (2021) Lipid metabolism and ferroptosis. Biology-Basel. https://doi.org/10.3390/biology10030184

    Article  PubMed  PubMed Central  Google Scholar 

  47. Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS et al (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13(1):81–90. https://doi.org/10.1038/nchembio.2238

    Article  CAS  PubMed  Google Scholar 

  48. Rouzer CA, Marnett LJ (2003) Mechanism of free radical oxygenation of polyunsaturated fatty acids by cyclooxygenases. Chem Rev 103(6):2239–2304. https://doi.org/10.1021/cr000068x

    Article  CAS  PubMed  Google Scholar 

  49. Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B al (2017) Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547(7664):453–457. https://doi.org/10.1038/nature23007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zou Y, Li H, Graham ET, Deik AA, Eaton JK, Wang W al (2020) Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat Chem Biol 16(3):302–309. https://doi.org/10.1038/s41589-020-0472-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kathman SG, Boshart J, Jing H, Cravatt BF (2020) Blockade of the lysophosphatidylserine lipase ABHD12 potentiates ferroptosis in cancer cells. ACS Chem Biol 15(4):871–877. https://doi.org/10.1021/acschembio.0c00086

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Zou Y, Henry WS, Ricq EL, Graham ET, Phadnis VV, Maretich P al (2020) Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature 585(7826):603–608. https://doi.org/10.1038/s41586-020-2732-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Ubellacker JM, Tasdogan A, Ramesh V, Shen B, Mitchell EC, Martin-Sandoval MS et al (2020) Lymph protects metastasizing melanoma cells from ferroptosis. Nature 585(7823):113–118. https://doi.org/10.1038/s41586-020-2623-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Magtanong L, Ko PJ, To M, Cao JY, Forcina GC, Tarangelo A et al (2019) Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol 26(3):420-432e429. https://doi.org/10.1016/j.chembiol.2018.11.016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hoy AJ, Nagarajan SR, Butler LM (2021) Tumour fatty acid metabolism in the context of therapy resistance and obesity. Nat Rev Cancer 21(12):753–766. https://doi.org/10.1038/s41568-021-00388-4

    Article  CAS  PubMed  Google Scholar 

  56. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I al (2017) ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 13(1):91–98. https://doi.org/10.1038/nchembio.2239

    Article  CAS  PubMed  Google Scholar 

  57. Reed A, Ichu TA, Milosevich N, Melillo B, Schafroth MA, Otsuka Y et al (2022) LPCAT3 inhibitors remodel the polyunsaturated phospholipid content of human cells and protect from ferroptosis. ACS Chem Biol 17(6):1607–1618. https://doi.org/10.1021/acschembio.2c00317

    Article  CAS  PubMed  Google Scholar 

  58. Wu J, Minikes AM, Gao M, Bian H, Li Y, Stockwell BR et al (2019) Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature 572(7769):402–406. https://doi.org/10.1038/s41586-019-1426-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Jiang X, Stockwell BR, Conrad M (2021) Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 22(4):266–282. https://doi.org/10.1038/s41580-020-00324-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Sha R, Xu Y, Yuan C, Sheng X, Wu Z, Peng J et al (2021) Predictive and prognostic impact of ferroptosis-related genes ACSL4 and GPX4 on breast cancer treated with neoadjuvant chemotherapy. EBioMedicine 71:103560. https://doi.org/10.1016/j.ebiom.2021.103560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Yan HF, Zou T, Tuo QZ, Xu S, Li H, Belaidi AA et al (2021) Ferroptosis: mechanisms and links with diseases. Signal Transduct Target Ther 6(1):49. https://doi.org/10.1038/s41392-020-00428-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Zhou B, Zhang JY, Liu XS, Chen HZ, Ai YL, Cheng K al (2018) Tom20 senses iron-activated ROS signaling to promote melanoma cell pyroptosis. Cell Res 28(12):1171–1185. https://doi.org/10.1038/s41422-018-0090-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang HL, Hu BX, Li ZL, Du T, Shan JL, Ye ZP et al (2022) PKC beta II phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat Cell Biol 24(1):88. https://doi.org/10.1038/s41556-021-00818-3

    Article  CAS  PubMed  Google Scholar 

  64. Wenzel SE, Tyurina YY, Zhao J, St Croix CM, Dar HH, Mao G (2017) PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171(3):628-641e626. https://doi.org/10.1016/j.cell.2017.09.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR (2016) Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci U S A 113(34):E4966–4975. https://doi.org/10.1073/pnas.1603244113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Gardner HW (1989) Oxygen radical chemistry of polyunsaturated fatty acids. Free Radic Biol Med 7(1):65–86. https://doi.org/10.1016/0891-5849(89)90102-0

    Article  CAS  PubMed  Google Scholar 

  67. Ayala A, Munoz MF, Arguelles S (2014) Lipid peroxidation: production, metabolism, and signaling mechanisms of malondialdehyde and 4-hydroxy-2-nonenal. Oxid Med Cell Longev 2014:360438. https://doi.org/10.1155/2014/360438

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Wong-Ekkabut J, Xu Z, Triampo W, Tang IM, Tieleman DP, Monticelli L (2007) Effect of lipid peroxidation on the properties of lipid bilayers: a molecular dynamics study. Biophys J 93(12):4225–4236. https://doi.org/10.1529/biophysj.107.112565

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Chng CP, Sadovsky Y, Hsia KJ, Huang C (2021) Site-specific peroxidation modulates lipid bilayer mechanics. Extreme Mech Lett. https://doi.org/10.1016/j.eml.2020.101148

    Article  PubMed  PubMed Central  Google Scholar 

  70. Kraft VAN, Bezjian CT, Pfeiffer S, Ringelstetter L, Muller C, Zandkarimi F (2020) GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. Acs Cent Sci 6(1):41–53. https://doi.org/10.1021/acscentsci.9b01063

    Article  CAS  PubMed  Google Scholar 

  71. Imai H, Matsuoka M, Kumagai T, Sakamoto T, Koumura T (2017) Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis. Curr Top Microbiol 403:143–170. https://doi.org/10.1007/82_2016_508

    Article  CAS  Google Scholar 

  72. Ingold I, Berndt C, Schmitt S, Doll S, Poschmann G, Buday K (2018) Selenium utilization by GPX4 is required to prevent hydroperoxide-induced ferroptosis. Cell 172(3):409. https://doi.org/10.1016/j.cell.2017.11.048

    Article  CAS  PubMed  Google Scholar 

  73. Ursini F, Maiorino M (2020) Lipid peroxidation and ferroptosis: the role of GSH and GPx4. Free Radical Bio Med 152:175–185

    Article  CAS  Google Scholar 

  74. Battaglia AM, Chirillo R, Aversa I, Sacco A, Costanzo F, Biamonte F (2020) Ferroptosis and cancer: mitochondria meet the “Iron Maiden” cell death. Cells. https://doi.org/10.3390/cells9061505

    Article  PubMed  PubMed Central  Google Scholar 

  75. Yao Y, Chen Z, Zhang H, Chen CL, Zeng M, Yunis J al (2021) Selenium-GPX4 axis protects follicular helper T cells from ferroptosis. Nat Immunol 22(9):1127–. https://doi.org/10.1038/s41590-021-00996-0

    Article  CAS  PubMed  Google Scholar 

  76. Alim I, Caulfield JT, Chen YX, Swarup V, Geschwind DH, Ivanova E et al (2019) Selenium drives a transcriptional adaptive program to block ferroptosis and treat stroke. Cell 177(5):1262. https://doi.org/10.1016/j.cell.2019.03.032

    Article  CAS  PubMed  Google Scholar 

  77. Li Y, Feng DC, Wang ZY, Zhao Y, Sun RM, Tian DH et al (2019) Ischemia-induced ACSL4 activation contributes to ferroptosis-mediated tissue injury in intestinal ischemia/reperfusion. Cell Death Differ 26(11):2284–2299. https://doi.org/10.1038/s41418-019-0299-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Hakimi AA, Reznik E, Lee CH, Creighton CJ, Brannon AR, Luna A et al (2016) An integrated metabolic atlas of clear cell renal cell carcinoma. Cancer Cell 29(1):104–116. https://doi.org/10.1016/j.ccell.2015.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Nishizawa S, Araki H, Ishikawa Y, Kitazawa S, Hata A, Soga T al (2018) Low tumor glutathione level as a sensitivity marker for glutamate-cysteine ligase inhibitors. Oncol Lett 15(6):8735–8743. https://doi.org/10.3892/ol.2018.8447

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Stockwell BR (2018) Ferroptosis: death by lipid peroxidation. Free Radical Bio Med 120:S7–S7. https://doi.org/10.1016/j.freeradbiomed.2018.04.034

    Article  Google Scholar 

  81. Gao MH, Monian P, Quadri N, Ramasamy R, Jiang XJ (2015) Glutaminolysis and transferrin regulate ferroptosis. Mol Cell 59(2):298–308. https://doi.org/10.1016/j.molcel.2015.06.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Badgley MA, Kremer DM, Maurer HC, DelGiorno KE, Lee HJ, Purohit V al (2020) Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 368(6486):85–. https://doi.org/10.1126/science.aaw9872

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Alborzinia H, Florez AF, Kreth S, Bruckner LM, Yildiz U, Gartlgruber M al (2022) MYCN mediates cysteine addiction and sensitizes neuroblastoma to ferroptosis. Nat Cancer 3(4):471–485. https://doi.org/10.1038/s43018-022-00355-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Kang YP, Mockabee-Macias A, Jiang C, Falzone A, Prieto-Farigua N, Stone E (2021) Non-canonical glutamate-cysteine ligase activity protects against ferroptosis. Cell Metab 33(1):174-189e177. https://doi.org/10.1016/j.cmet.2020.12.007

    Article  CAS  PubMed  Google Scholar 

  85. Zhang YL, Shi JJ, Liu XG, Feng L, Gong ZH, Koppula P al (2018) BAP1 links metabolic regulation of ferroptosis to tumour suppression. Nat Cell Biol 20(10):1181–. https://doi.org/10.1038/s41556-018-0178-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Jiang L, Kon N, Li TY, Wang SJ, Su T, Hibshoosh H al (2015) Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520(7545):57–. https://doi.org/10.1038/nature14344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Chu B, Kon N, Chen DL, Li TY, Liu T, Jiang L al (2019) ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat Cell Biol 21(5):579–. https://doi.org/10.1038/s41556-019-0305-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wang X, Chen Y, Wang X, Tian H, Wang Y, Jin J (2021) Stem cell factor SOX2 confers ferroptosis resistance in lung cancer via upregulation of SLC7A11. Cancer Res 81(20):5217–5229. https://doi.org/10.1158/0008-5472.CAN-21-0567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wu M, Zhang X, Zhang W, Chiou YS, Qian W, Liu X al (2022) Cancer stem cell regulated phenotypic plasticity protects metastasized cancer cells from ferroptosis. Nat Commun 13(1):1371. https://doi.org/10.1038/s41467-022-29018-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Sharbeen G, McCarroll JA, Akerman A, Kopecky C, Youkhana J, Kokkinos J et al (2021) Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma determine response to SLC7A11 inhibition. Cancer Res 81(13):3461–3479. https://doi.org/10.1158/0008-5472.CAN-20-2496

    Article  CAS  PubMed  Google Scholar 

  91. Shimada K, Hayano M, Pagano NC, Stockwell BR (2016) Cell-Line selectivity improves the predictive power of pharmacogenomic analyses and helps identify NADPH as biomarker for ferroptosis sensitivity. Cell Chem Biology 23(2):225–235. https://doi.org/10.1016/j.chembiol.2015.11.016

    Article  CAS  Google Scholar 

  92. Ding CKC, Rose J, Sun TA, Wu JL, Chen PH, Lin CC et al (2020) MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis. Nat Metabolism 2(3):270. https://doi.org/10.1038/s42255-020-0181-1

    Article  CAS  Google Scholar 

  93. Lin CCE, Ding CKC, Sun TA, Wu JL, Chen KY, Zhou P, al, (2021) The regulation of ferroptosis by MESH1 through the activation of the integrative stress response. Cell Death Dis. https://doi.org/10.1038/s41419-021-04018-7

    Article  PubMed  PubMed Central  Google Scholar 

  94. Elguindy MM, Nakamaru-Ogiso E (2015) Apoptosis-inducing Factor (AIF) and its family member protein, AMID, are rotenone-sensitive NADH: ubiquinone oxidoreductases (NDH-2). J Biol Chem 290(34):20815–20826. https://doi.org/10.1074/jbc.M115.641498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Shimada K, Skouta R, Kaplan A, Yang WS, Hayano M, Dixon SJ et al (2016) Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol 12(7):497. https://doi.org/10.1038/Nchembio.2079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Koppula P, Lei G, Zhang Y, Yan Y, Mao C, Kondiparthi L al (2022) A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers. Nat Commun 13(1):2206. https://doi.org/10.1038/s41467-022-29905-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Mishima E, Ito J, Wu Z, Nakamura T, Wahida A, Doll S al (2022) A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature. https://doi.org/10.1038/s41586-022-05022-3

    Article  PubMed  PubMed Central  Google Scholar 

  98. Gao MH, Yi JM, Zhu JJ, Minikes AM, Monian P, Thompson CB et al (2019) Role of mitochondria in ferroptosis. Mol Cell 73(2):354. https://doi.org/10.1016/j.molcel.2018.10.042

    Article  CAS  PubMed  Google Scholar 

  99. Zhang L, Zhou F, van Laar T, Zhang J, van Dam H, Ten Dijke P (2011) Fas-associated factor 1 antagonizes Wnt signaling by promoting beta-catenin degradation. Mol Biol Cell 22(9):1617–1624. https://doi.org/10.1091/mbc.E10-12-0985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Zhang L, Zhou F, Li Y, Drabsch Y, Zhang J, van Dam H et al (2012) Fas-associated factor 1 is a scaffold protein that promotes beta-transducin repeat-containing protein (beta-TrCP)-mediated beta-catenin ubiquitination and degradation. J Biol Chem 287(36):30701–30710. https://doi.org/10.1074/jbc.M112.353524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kim H, Rodriguez-Navas C, Kollipara RK, Kapur P, Pedrosa I, Brugarolas J (2015) Unsaturated fatty acids stimulate tumor growth through stabilization of beta-catenin. Cell Rep 13(3):495–503. https://doi.org/10.1016/j.celrep.2015.09.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Soula M, Weber RA, Zilka O, Alwaseem H, La K, Yen F al (2020) Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat Chem Biol 16(12):1351–. https://doi.org/10.1038/s41589-020-0613-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Roh JL, Kim EH, Jang H, Shin D (2017) Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol 11:254–262. https://doi.org/10.1016/j.redox.2016.12.010

    Article  CAS  PubMed  Google Scholar 

  104. Dodson M, Castro-Portuguez R, Zhang DD (2019) NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol 23:101107. https://doi.org/10.1016/j.redox.2019.101107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Shin D, Kim EH, Lee J, Roh JL (2018) Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic Biol Med 129:454–462. https://doi.org/10.1016/j.freeradbiomed.2018.10.426

    Article  CAS  PubMed  Google Scholar 

  106. Anandhan A, Dodson M, Schmidlin CJ, Liu P, Zhang DD (2020) Breakdown of an ironclad defense system: the critical role of NRF2 in mediating ferroptosis. Cell Chem Biol 27(4):436–447. https://doi.org/10.1016/j.chembiol.2020.03.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Wu KC, Cui JY, Klaassen CD (2011) Beneficial role of Nrf2 in regulating NADPH generation and consumption. Toxicol Sci 123(2):590–600. https://doi.org/10.1093/toxsci/kfr183

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Song X, Long D (2020) Nrf2 and ferroptosis: a new research direction for neurodegenerative diseases. Front Neurosci 14:267. https://doi.org/10.3389/fnins.2020.00267

    Article  PubMed  PubMed Central  Google Scholar 

  109. Kerins MJ, Ooi A (2018) The roles of NRF2 in modulating cellular iron homeostasis. Antioxid Redox Sign 29(17):1756–1773. https://doi.org/10.1089/ars.2017.7176

    Article  CAS  Google Scholar 

  110. Chen D, Chu B, Yang X, Liu Z, Jin Y, Kon N (2021) iPLA2β-mediated lipid detoxification controls p53-driven ferroptosis independent of GPX4. Nat Commun 12(1):1–15

    Google Scholar 

  111. Carlson BA, Tobe R, Yefremova E, Tsuji PA, Hoffmann VJ, Schweizer U al (2016) Glutathione peroxidase 4 and vitamin E cooperatively prevent hepatocellular degeneration. Redox Biol 9:22–31. https://doi.org/10.1016/j.redox.2016.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Llabani E, Hicklin RW, Lee HY, Motika SE, Crawford LA, Weerapana E et al (2019) Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis. Nat Chem 11(6):521–532. https://doi.org/10.1038/s41557-019-0261-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Jelinek A, Heyder L, Daude M, Plessner M, Krippner S, Grosse R al (2018) Mitochondrial rescue prevents glutathione peroxidase-dependent ferroptosis. Free Radic Biol Med 117:45–57. https://doi.org/10.1016/j.freeradbiomed.2018.01.019

    Article  CAS  PubMed  Google Scholar 

  114. Butler LM, Perone Y, Dehairs J, Lupien LE, de Laat V, Talebi A (2020) Lipids and cancer: emerging roles in pathogenesis, diagnosis and therapeutic intervention. Adv Drug Deliv Rev 159:245–293. https://doi.org/10.1016/j.addr.2020.07.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Xu H, Chen Y, Gu M, Liu C, Chen Q, Zhan M (2021) Fatty acid metabolism reprogramming in advanced prostate cancer. Metabolites. https://doi.org/10.3390/metabo11110765

    Article  PubMed  PubMed Central  Google Scholar 

  116. Hao Y, Li D, Xu Y, Ouyang J, Wang Y, Zhang Y al (2019) Investigation of lipid metabolism dysregulation and the effects on immune microenvironments in pan-cancer using multiple omics data. BMC Bioinformatics 20(Suppl 7):195. https://doi.org/10.1186/s12859-019-2734-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Currie E, Schulze A, Zechner R, Walther TC, Farese RV Jr (2013) Cellular fatty acid metabolism and cancer. Cell Metab 18(2):153–161. https://doi.org/10.1016/j.cmet.2013.05.017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Su X, Abumrad NA (2009) Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab 20(2):72–77. https://doi.org/10.1016/j.tem.2008.11.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Bian X, Liu R, Meng Y, Xing D, Xu D, Lu Z (2021) Lipid metabolism and cancer. J Exp Med. https://doi.org/10.1084/jem.20201606

    Article  PubMed  PubMed Central  Google Scholar 

  120. Gallagher EJ, Zelenko Z, Neel BA, Antoniou IM, Rajan L, Kase N et al (2017) Elevated tumor LDLR expression accelerates LDL cholesterol-mediated breast cancer growth in mouse models of hyperlipidemia. Oncogene 36(46):6462–6471. https://doi.org/10.1038/onc.2017.247

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Guillaumond F, Bidaut G, Ouaissi M, Servais S, Gouirand V, Olivares O al (2015) Cholesterol uptake disruption, in association with chemotherapy, is a promising combined metabolic therapy for pancreatic adenocarcinoma. P Natl Acad Sci USA 112(8):2473–2478. https://doi.org/10.1073/pnas.1421601112

    Article  CAS  Google Scholar 

  122. Zhou T, Zhan JH, Fang WF, Zhao YY, Yang YP, Hou X (2017) Serum low-density lipoprotein and low-density lipoprotein expression level at diagnosis are favorable prognostic factors in patients with small-cell lung cancer (SCLC). BMC Cancer. https://doi.org/10.1186/s12885-017-3239-z

    Article  PubMed  PubMed Central  Google Scholar 

  123. Rink JS, Lin AY, McMahon KM, Calvert AE, Yang S, Taxter T et al (2021) Targeted reduction of cholesterol uptake in cholesterol-addicted lymphoma cells blocks turnover of oxidized lipids to cause ferroptosis. J Biol Chem 296:100100. https://doi.org/10.1074/jbc.RA120.014888

    Article  CAS  PubMed  Google Scholar 

  124. Liu W, Chakraborty B, Safi R, Kazmin D, Chang CY, McDonnell DP (2021) Dysregulated cholesterol homeostasis results in resistance to ferroptosis increasing tumorigenicity and metastasis in cancer. Nat Commun 12(1):5103. https://doi.org/10.1038/s41467-021-25354-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Khwairakpam AD, Banik K, Girisa S, Shabnam B, Shakibaei M, Fan L al (2020) The vital role of ATP citrate lyase in chronic diseases. J Mol Med 98(1):71–95

    Article  CAS  PubMed  Google Scholar 

  126. Lee H, Zandkarimi F, Zhang Y, Meena JK, Kim J, Zhuang L al (2020) Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat Cell Biol 22(2):225–234. https://doi.org/10.1038/s41556-020-0461-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ning Z, Guo X, Liu X, Lu C, Wang A, Wang X al (2022) USP22 regulates lipidome accumulation by stabilizing PPARgamma in hepatocellular carcinoma. Nat Commun 13(1):2187. https://doi.org/10.1038/s41467-022-29846-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Collins JM, Neville MJ, Hoppa MB, Frayn KN (2010) De novo lipogenesis and stearoyl-CoA desaturase are coordinately regulated in the human adipocyte and protect against palmitate-induced cell injury. J Biol Chem 285(9):6044–6052. https://doi.org/10.1074/jbc.M109.053280

    Article  CAS  PubMed  Google Scholar 

  129. Lee JY, Nam M, Son HY, Hyun K, Jang SY, Kim JW et al (2020) Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer. Proc Natl Acad Sci U S A 117(51):32433–32442. https://doi.org/10.1073/pnas.2006828117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Peck B, Schulze A (2016) Lipid desaturation - the next step in targeting lipogenesis in cancer? FEBS J 283(15):2767–2778. https://doi.org/10.1111/febs.13681

    Article  CAS  PubMed  Google Scholar 

  131. Zhao Y, Li M, Yao X, Fei Y, Lin Z, Li Z (2020) HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications. Cell Rep 33(10):108487. https://doi.org/10.1016/j.celrep.2020.108487

    Article  CAS  PubMed  Google Scholar 

  132. Yang J, Wang LH, Jia RB (2020) Role of de novo cholesterol synthesis enzymes in cancer. J Cancer 11(7):1761–1767. https://doi.org/10.7150/jca.38598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Jun SY, Brown AJ, Chua NK, Yoon JY, Lee JJ, Yang JO et al (2021) Reduction of squalene epoxidase by cholesterol accumulation accelerates colorectal cancer progression and metastasis. Gastroenterology 160(4):1194. https://doi.org/10.1053/j.gastro.2020.09.009

    Article  CAS  PubMed  Google Scholar 

  134. Garcia-Bermudez J, Baudrier L, Bayraktar EC, Shen Y, La K, Guarecuco R al (2019) Squalene accumulation in cholesterol auxotrophic lymphomas prevents oxidative cell death. Nature 567(7746):118–122. https://doi.org/10.1038/s41586-019-0945-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Zhang N, Zhang HW, Liu Y, Su P, Zhang JS, Wang XL et al (2019) SREBP1, targeted by miR-18a-5p, modulates epithelial-mesenchymal transition in breast cancer via forming a co-repressor complex with Snail and HDAC1/2. Cell Death Differ 26(5):843–859. https://doi.org/10.1038/s41418-018-0158-8

    Article  CAS  PubMed  Google Scholar 

  136. Cheng CM, Geng F, Li Z, Zhong YG, Wang HB, Cheng X al (2022) Ammonia stimulates SCAP/Insig dissociation and SREBP-1 activation to promote lipogenesis and tumour growth. Nat Metabolism. https://doi.org/10.1038/s42255-022-00568-y

    Article  Google Scholar 

  137. Carracedo A, Cantley LC, Pandolfi PP (2013) Cancer metabolism: fatty acid oxidation in the limelight. Nat Rev Cancer 13(4):227–232. https://doi.org/10.1038/nrc3483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Wang C, Shao L, Pan C, Ye J, Ding Z, Wu J al (2019) Elevated level of mitochondrial reactive oxygen species via fatty acid beta-oxidation in cancer stem cells promotes cancer metastasis by inducing epithelial-mesenchymal transition. Stem Cell Res Ther 10(1):175. https://doi.org/10.1186/s13287-019-1265-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Jiang N, Xie B, Xiao W, Fan M, Xu S, Duan Y al (2022) Fatty acid oxidation fuels glioblastoma radioresistance with CD47-mediated immune evasion. Nat Commun 13(1):1511. https://doi.org/10.1038/s41467-022-29137-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Miess H, Dankworth B, Gouw AM, Rosenfeldt M, Schmitz W, Jiang M al (2018) The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma. Oncogene 37(40):5435–5450. https://doi.org/10.1038/s41388-018-0315-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Geng F, Cheng X, Wu XN, Yoo JY, Cheng CM, Guo JYH et al (2016) Inhibition of SOAT1 Suppresses glioblastoma growth via blocking SREBP-1-mediated lipogenesis. Clin Cancer Res 22(21):5337–5348. https://doi.org/10.1158/1078-0432.Ccr-15-2973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Cheng X, Geng F, Pan MX, Wu XN, Zhong YG, Wang CY et al (2020) Targeting DGAT1 ameliorates glioblastoma by increasing fat catabolism and oxidative stress. Cell Metab 32(2):229. https://doi.org/10.1016/j.cmet.2020.06.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Olzmann JA, Carvalho P (2019) Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol 20(3):137–155. https://doi.org/10.1038/s41580-018-0085-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Bensaad K, Favaro E, Lewis CA, Peck B, Lord S, Collins JM et al (2014) Fatty acid uptake and lipid storage induced by HIF-1alpha contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep 9(1):349–365. https://doi.org/10.1016/j.celrep.2014.08.056

    Article  CAS  PubMed  Google Scholar 

  145. Dierge E, Debock E, Guilbaud C, Corbet C, Mignolet E, Mignard L al (2021) Peroxidation of n-3 and n-6 polyunsaturated fatty acids in the acidic tumor environment leads to ferroptosis-mediated anticancer effects. Cell Metab 33(8):1701–1715e1705. https://doi.org/10.1016/j.cmet.2021.05.016

    Article  CAS  PubMed  Google Scholar 

  146. Mukhopadhyay S, Schlaepfer IR, Bergman BC, Panda PK, Praharaj PP, Naik PP et al (2017) ATG14 facilitated lipophagy in cancer cells induce ER stress mediated mitoptosis through a ROS dependent pathway. Free Radical Bio Med 104:199–213. https://doi.org/10.1016/j.freeradbiomed.2017.01.007

    Article  CAS  Google Scholar 

  147. Panda PK, Patra S, Naik PP, Praharaj PP, Mukhopadhyay S, Meher BR et al (2020) Deacetylation of LAMP1 drives lipophagy-dependent generation of free fatty acids by Abrus agglutinin to promote senescence in prostate cancer. J Cell Physiol 235(3):2776–2791. https://doi.org/10.1002/jcp.29182

    Article  CAS  PubMed  Google Scholar 

  148. Bai Y, Meng L, Han L, Jia Y, Zhao Y, Gao H al (2019) Lipid storage and lipophagy regulates ferroptosis. Biochem Biophys Res Commun 508(4):997–1003. https://doi.org/10.1016/j.bbrc.2018.12.039

    Article  CAS  PubMed  Google Scholar 

  149. Maan M, Peters JM, Dutta M, Patterson AD (2018) Lipid metabolism and lipophagy in cancer. Biochem Bioph Res Co 504(3):582–589. https://doi.org/10.1016/j.bbrc.2018.02.097

    Article  CAS  Google Scholar 

  150. Nomura DK, Long JZ, Niessen S, Hoover HS, Ng SW, Cravatt BF (2010) Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140(1):49–61. https://doi.org/10.1016/j.cell.2009.11.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Ding LG, Sun WF, Balaz M, He AY, Klug M, Wieland S et al (2021) Peroxisomal beta-oxidation acts as a sensor for intracellular fatty acids and regulates lipolysis. Nat Metabolism 3(12):1648. https://doi.org/10.1038/s42255-021-00489-2

    Article  CAS  Google Scholar 

  152. Xuan Y, Wang H, Yung MM, Chen F, Chan WS, Chan YS et al (2022) SCD1/FADS2 fatty acid desaturases equipoise lipid metabolic activity and redox-driven ferroptosis in ascites-derived ovarian cancer cells. Theranostics 12(7):3534–3552. https://doi.org/10.7150/thno.70194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Yi J, Zhu J, Wu J, Thompson CB, Jiang X (2020) Oncogenic activation of PI3K-AKT-mTOR signaling suppresses ferroptosis via SREBP-mediated lipogenesis. Proc Natl Acad Sci U S A 117(49):31189–31197. https://doi.org/10.1073/pnas.2017152117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Wang K, Zhang Z, Tsai HI, Liu Y, Gao J, Wang M al (2021) Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells. Cell Death Differ 28(4):1222–1236. https://doi.org/10.1038/s41418-020-00644-4

    Article  CAS  PubMed  Google Scholar 

  155. Li C, Dong X, Du W, Shi X, Chen K, Zhang W al (2020) LKB1-AMPK axis negatively regulates ferroptosis by inhibiting fatty acid synthesis. Signal Transduct Target Ther 5(1):187. https://doi.org/10.1038/s41392-020-00297-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Ma X, Xiao L, Liu L, Ye L, Su P, Bi E al (2021) CD36-mediated ferroptosis dampens intratumoral CD8(+) T cell effector function and impairs their antitumor ability. Cell Metab 33(5):1001–1012e1005. https://doi.org/10.1016/j.cmet.2021.02.015

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Xu S, Chaudhary O, Rodriguez-Morales P, Sun X, Chen D, Zappasodi R al (2021) Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8(+) T cells in tumors. Immunity 54(7):1561–1577e1567. https://doi.org/10.1016/j.immuni.2021.05.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Kamili A, Roslan N, Frost S, Cantrill LC, Wang DW, Della-Franca A et al (2015) TPD52 expression increases neutral lipid storage within cultured cells. J Cell Sci 128(17):3223–3238. https://doi.org/10.1242/jcs.167692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Zechner R, Madeo F, Kratky D (2017) Cytosolic lipolysis and lipophagy: two sides of the same coin. Nat Rev Mol Cell Biol 18(11):671–684. https://doi.org/10.1038/nrm.2017.76

    Article  CAS  PubMed  Google Scholar 

  160. Liu K, Czaja MJ (2013) Regulation of lipid stores and metabolism by lipophagy. Cell Death Differ 20(1):3–11. https://doi.org/10.1038/cdd.2012.63

    Article  CAS  PubMed  Google Scholar 

  161. Yang MH, Chen P, Liu J, Zhu S, Kroemer GO, Klionsky DN et al (2019) Clockophagy is a novel selective autophagy process favoring ferroptosis. Sci Adv. https://doi.org/10.1126/sciadv.aaw2238

    Article  PubMed  PubMed Central  Google Scholar 

  162. Tan SK, Mahmud I, Fontanesi F, Puchowicz M, Neumann CKA, Griswold AJ et al (2021) Obesity-dependent adipokine chemerin suppresses fatty acid oxidation to confer ferroptosis resistance. Cancer Discov 11(8):2072–2093. https://doi.org/10.1158/2159-8290.CD-20-1453

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Justus CR, Dong L, Yang LV (2013) Acidic tumor microenvironment and pH-sensing G protein-coupled receptors. Front Physiol 4:354. https://doi.org/10.3389/fphys.2013.00354

    Article  PubMed  PubMed Central  Google Scholar 

  164. Morrissey SM, Zhang F, Ding C, Montoya-Durango DE, Hu X, Yang C et al (2021) Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming. Cell Metab 33(10):2040-2058 e2010. https://doi.org/10.1016/j.cmet.2021.09.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Pucino V, Certo M, Bulusu V, Cucchi D, Goldmann K, Pontarini E al (2019) Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4(+) T Cell Metabolic Rewiring. Cell Metab 30(6):1055–. https://doi.org/10.1016/j.cmet.2019.10.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Zhang HY, Deng T, Liu R, Ning T, Yang HO, Liu DY et al (2020) CAF secreted miR-522 suppresses ferroptosis and promotes acquired chemo-resistance in gastric cancer. Mol Cancer. https://doi.org/10.1186/s12943-020-01168-8

    Article  PubMed  PubMed Central  Google Scholar 

  167. Wang W, Kryczek I, Dostal L, Lin H, Tan L, Zhao L (2016) Effector T cells abrogate stroma-mediated chemoresistance in ovarian cancer. Cell 165(5):1092–1105. https://doi.org/10.1016/j.cell.2016.04.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Wang W, Green M, Choi JE, Gijon M, Kennedy PD, Johnson JK et al (2019) CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569(7755):270–274. https://doi.org/10.1038/s41586-019-1170-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Kim D, Kim WD, Kim SK, Moon DH, Lee SJ (2020) TGF-beta 1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells. Cell Death Dis. https://doi.org/10.1038/s41419-020-2618-6

    Article  PubMed  PubMed Central  Google Scholar 

  170. Angeli JPF, Schneider M, Proneth B, Tyurina YY, Tyurin VA, Hammond V et al (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16(12):1180-U1120. https://doi.org/10.1038/ncb3064

    Article  CAS  PubMed Central  Google Scholar 

  171. Angeli JPF, Krysko DV, Conrad M (2019) Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer 19(7):405–414

    Article  Google Scholar 

  172. Bottcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, Sammicheli S (2018) NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172(5):1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Luo X, Gong HB, Gao HY, Wu YP, Sun WY, Li ZQ et al (2021) Oxygenated phosphatidylethanolamine navigates phagocytosis of ferroptotic cells by interacting with TLR2. Cell Death Differ 28(6):1971–1989. https://doi.org/10.1038/s41418-020-00719-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Baek AE, Yu YA, He S, Wardell SE, Chang CY, Kwon S al (2017) The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells. Nat Commun 8(1):864. https://doi.org/10.1038/s41467-017-00910-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Kapralov AA, Yang Q, Dar HH, Tyurina YY, Anthonymuthu TS, Kim R et al (2020) Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat Chem Biol 16(3):278–290. https://doi.org/10.1038/s41589-019-0462-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Muri J, Thut H, Bornkamm GW, Kopf M (2019) B1 and marginal zone B cells but not follicular B2 cells require Gpx4 to prevent lipid peroxidation and ferroptosis. Cell Rep 29(9):2731-2744e2734. https://doi.org/10.1016/j.celrep.2019.10.070

    Article  CAS  PubMed  Google Scholar 

  177. Galluzzi L, Vitale I, Warren S, Adjemian S, Agostinis P, Martinez AB et al (2020) Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J Immun Can. 8(1):e000337

    Google Scholar 

  178. Garg AD, Nowis D, Golab J, Vandenabeele P, Krysko DV, Agostinis P (2010) Immunogenic cell death, DAMPs and anticancer therapeutics: an emerging amalgamation. Bba-Rev Cancer 1805(1):53–71

    CAS  Google Scholar 

  179. Snyder AG, Hubbard NW, Messmer MN, Kofman SB, Hagan CE, Orozco SL et al (2019) Intratumoral activation of the necroptotic pathway components RIPK1 and RIPK3 potentiates antitumor immunity. Sci Immunol 4(36):eaaw2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Wen Q, Liu J, Kang R, Zhou B, Tang D (2019) The release and activity of HMGB1 in ferroptosis. Biochem Biophys Res Commun 510(2):278–283. https://doi.org/10.1016/j.bbrc.2019.01.090

    Article  CAS  PubMed  Google Scholar 

  181. Turubanova VD, Balalaeva IV, Mishchenko TA, Catanzaro E, Alzeibak R, Peskova NN et al (2019) Immunogenic cell death induced by a new photodynamic therapy based on photosens and photodithazine. J Immunother Cancer 7(1):350. https://doi.org/10.1186/s40425-019-0826-3

    Article  PubMed  PubMed Central  Google Scholar 

  182. Efimova I, Catanzaro E, Van der Meeren L, Turubanova VD, Hammad H, Mishchenko TA et al (2020) Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity. J Immunother Cancer. https://doi.org/10.1136/jitc-2020-001369

    Article  PubMed  PubMed Central  Google Scholar 

  183. Li DS, Li YS (2020) The interaction between ferroptosis and lipid metabolism in cancer. Signal Transduct Tar. https://doi.org/10.1038/s41392-020-00216-5

    Article  Google Scholar 

  184. Dai EY, Han L, Liu J, Xie YC, Kroemer G, Klionsky DJ et al (2020) Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy 16(11):2069–2083. https://doi.org/10.1080/15548627.2020.1714209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Dai EY, Han L, Liu J, Xie YC, Zeh HJ, Kang R et al (2020) Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway. Nat Commun. https://doi.org/10.1038/s41467-020-20154-8

    Article  PubMed  PubMed Central  Google Scholar 

  186. Granchi C (2018) ATP citrate lyase (ACLY) inhibitors: an anti-cancer strategy at the crossroads of glucose and lipid metabolism. Eur J Med Chem 157:1276–1291. https://doi.org/10.1016/j.ejmech.2018.09.001

    Article  CAS  PubMed  Google Scholar 

  187. Huang ZG, Zhang M, Plec AA, Estill SJ, Cai L, Repa JJ et al (2018) ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism. P Natl Acad Sci USA 115(40):E9499–E9506. https://doi.org/10.1073/pnas.1806635115

    Article  CAS  Google Scholar 

  188. Miller KD, Pniewski K, Perry CE, Papp SB, Shaffer JD, Velasco-Silva JN et al (2021) Targeting ACSS2 with a transition-state mimetic inhibits triple-negative breast cancer growth. Cancer Res 81(5):1252–1264. https://doi.org/10.1158/0008-5472.Can-20-1847

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Lally JSV, Ghoshal S, DePeralta DK, Moaven O, Wei L, Masia R et al (2019) Inhibition of acetyl-CoA carboxylase by phosphorylation or the inhibitor ND-654 suppresses lipogenesis and hepatocellular carcinoma. Cell Metab 29(1):174. https://doi.org/10.1016/j.cmet.2018.08.020

    Article  CAS  PubMed  Google Scholar 

  190. Svensson RU, Parker SJ, Eichner LJ, Kolar MJ, Wallace M, Brun SN et al (2016) Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models. Nat Med 22(10):1108–1119. https://doi.org/10.1038/nm.4181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Gouw AM, Margulis K, Liu NS, Raman SJ, Mancuso A, Toal GG et al (2019) The MYC oncogene cooperates with sterol-regulated element-binding protein to regulate lipogenesis essential for neoplastic growth. Cell Metab 30(3):556. https://doi.org/10.1016/j.cmet.2019.07.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Schug ZT, Peck B, Jones DT, Zhang Q, Grosskurth S, Alam IS et al (2015) Acetyl-CoA synthetase 2 promotes acetate utilization and maintains cancer cell growth under metabolic stress. Cancer Cell 27(1):57–71. https://doi.org/10.1016/j.ccell.2014.12.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Menendez JA, Lupu R (2017) Fatty acid synthase (FASN) as a therapeutic target in breast cancer. Expert Opin Ther Tar 21(11):1001–1016. https://doi.org/10.1080/14728222.2017.1381087

    Article  CAS  Google Scholar 

  194. Zaytseva YY, Rychahou PG, Le AT, Scott TL, Flight RM, Kim JT et al (2018) Preclinical evaluation of novel fatty acid synthase inhibitors in primary colorectal cancer cells and a patient-derived xenograft model of colorectal cancer. Oncotarget 9(37):24787–24800. https://doi.org/10.18632/oncotarget.25361

    Article  PubMed  PubMed Central  Google Scholar 

  195. Heuer TS, Ventura R, Mordec K, Lai J, Fridlib M, Buckley D (2017) FASN inhibition and taxane treatment combine to enhance anti-tumor efficacy in diverse xenograft tumor models through disruption of tubulin palmitoylation and microtubule organization and FASN inhibition-mediated effects on oncogenic signaling and gene expression. Ebiomedicine 16:51–62

    Article  PubMed  Google Scholar 

  196. Kim S, Kang WK, Lee J, Park SH, Park JO, Park YS et al (2014) Simvastatin plus capecitabine-cisplatin (XP) versus placebo plus capecitabine-cisplatin (XP) in patients with previously untreated advanced gastric cancer: a double-blind randomized phase 3 study. J Clin Oncol. https://doi.org/10.1200/jco.2014.32.15_suppl.4066

    Article  PubMed  PubMed Central  Google Scholar 

  197. Perez MA, Magtanong L, Dixon SJ, Watts JL (2020) Dietary lipids induce ferroptosis in caenorhabditis elegans and human cancer cells. Dev Cell 54(4):447. https://doi.org/10.1016/j.devcel.2020.06.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Fang X, Xu Y, Wang S, Wan J, He C, Chen M (2017) Pluronic F68-Linoleic acid nano-spheres mediated delivery of gambogic acid for cancer therapy. AAPS PharmSciTech 18(1):147–155. https://doi.org/10.1208/s12249-015-0473-z

    Article  CAS  PubMed  Google Scholar 

  199. Berquin IM, Edwards IJ, Chen YQ (2008) Multi-targeted therapy of cancer by omega-3 fatty acids. Cancer Lett 269(2):363–377. https://doi.org/10.1016/j.canlet.2008.03.044

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Wei LY, Wu ZP, Chen YQ (2022) Multi-targeted therapy of cancer by omega-3 fatty acids-an update. Cancer Lett 526:193–204. https://doi.org/10.1016/j.canlet.2021.11.023

    Article  CAS  PubMed  Google Scholar 

  201. Lang X, Green MD, Wang W, Yu J, Choi JE, Jiang L (2019) Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov 9(12):1673–1685. https://doi.org/10.1158/2159-8290.CD-19-0338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Lei G, Mao C, Yan Y, Zhuang L, Gan B (2021) Ferroptosis, radiotherapy, and combination therapeutic strategies. Protein Cell 12(11):836–857. https://doi.org/10.1007/s13238-021-00841-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Lei G, Zhang Y, Koppula P, Liu X, Zhang J, Lin SH et al (2020) The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res 30(2):146–162. https://doi.org/10.1038/s41422-019-0263-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Lovey J, Nie D, Tovari J, Kenessey I, Timar J, Kandouz M al (2013) Radiosensitivity of human prostate cancer cells can be modulated by inhibition of 12-lipoxygenase. Cancer Lett 335(2):495–501. https://doi.org/10.1016/j.canlet.2013.03.012

    Article  CAS  PubMed  Google Scholar 

  205. Padanad MS, Konstantinidou G, Venkateswaran N, Melegari M, Rindhe S, Mitsche M et al (2016) Fatty acid oxidation mediated by Acyl-CoA synthetase long chain 3 is required for mutant KRAS lung tumorigenesis. Cell Rep 16(6):1614–1628. https://doi.org/10.1016/j.celrep.2016.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Liu G, Kuang S, Cao RB, Wang J, Peng QC, Sun CM (2019) Sorafenib kills liver cancer cells by disrupting SCD1-mediated synthesis of monounsaturated fatty acids via the ATP-AMPK-mTOR-SREBP1 signaling pathway. FASEB J 33(9):10089–10103. https://doi.org/10.1096/fj.201802619RR

    Article  CAS  PubMed  Google Scholar 

  207. Tesfay L, Paul BT, Konstorum A, Deng Z, Cox AO, Lee J (2019) Stearoyl-CoA desaturase 1 protects ovarian cancer cells from ferroptotic cell death. Cancer Res 79(20):5355–5366. https://doi.org/10.1158/0008-5472.CAN-19-0369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Zhao L, Zhou X, Xie F, Zhang L, Yan H, Huang J al (2022) Ferroptosis in cancer and cancer immunotherapy. Cancer Commun (Lond) 42(2):88–116. https://doi.org/10.1002/cac2.12250

    Article  PubMed  PubMed Central  Google Scholar 

  209. Hassannia B, Wiernicki B, Ingold I, Qu F, Van Herck S, Tyurina YY et al (2018) Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J Clin Invest 128(8):3341–3355. https://doi.org/10.1172/Jci99032

    Article  PubMed  PubMed Central  Google Scholar 

  210. Weiwer M, Bittker JA, Lewis TA, Shimada K, Yang WS, MacPherson L al (2012) Development of small-molecule probes that selectively kill cells induced to express mutant RAS. Bioorg Med Chem Lett 22(4):1822–1826. https://doi.org/10.1016/j.bmcl.2011.09.047

    Article  CAS  PubMed  Google Scholar 

  211. Woo JH, Shimoni Y, Yang WS, Subramaniam P, Iyer A, Nicoletti P (2015) Elucidating compound mechanism of action by network perturbation analysis. Cell 162(2):441–451. https://doi.org/10.1016/j.cell.2015.05.056

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Gao J, Yang F, Che J, Han Y, Wang Y, Chen N (2018) Selenium-encoded isotopic signature targeted profiling. ACS Cent Sci 4(8):960–970. https://doi.org/10.1021/acscentsci.8b00112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Harris IS, Treloar AE, Inoue S, Sasaki M, Gorrini C, Lee KC et al (2015) Glutathione and thioredoxin antioxidant pathways synergize to drive cancer initiation and progression. Cancer Cell 27(2):211–222. https://doi.org/10.1016/j.ccell.2014.11.019

    Article  CAS  PubMed  Google Scholar 

  214. Guo J, Xu B, Han Q, Zhou H, Xia Y, Gong C (2018) Ferroptosis: a novel anti-tumor action for cisplatin. Cancer Res Treat 50(2):445–460. https://doi.org/10.4143/crt.2016.572

    Article  CAS  PubMed  Google Scholar 

  215. Lo M, Ling V, Low C, Wang YZ, Gout PW (2010) Potential use of the anti-inflammatory drug, sulfasalazine, for targeted therapy of pancreatic cancer. Curr Oncol 17(3):9–16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Yu H, Yang C, Jian L, Guo S, Chen R, Li K (2019) Sulfasalazineinduced ferroptosis in breast cancer cells is reduced by the inhibitory effect of estrogen receptor on the transferrin receptor. Oncol Rep 42(2):826–838. https://doi.org/10.3892/or.2019.7189

    Article  CAS  PubMed  Google Scholar 

  217. Louandre C, Ezzoukhry Z, Godin C, Barbare JC, Maziere JC, Chauffert B al (2013) Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int J Cancer 133(7):1732–1742. https://doi.org/10.1002/ijc.28159

    Article  CAS  PubMed  Google Scholar 

  218. Zhang Y, Tan H, Daniels JD, Zandkarimi F, Liu H, Brown LM et al (2019) Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem Biol 26(5):623-633e629. https://doi.org/10.1016/j.chembiol.2019.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Sun X, Ou Z, Xie M, Kang R, Fan Y, Niu X al (2015) HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene 34(45):5617–5625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Basuli D, Tesfay L, Deng Z, Paul B, Yamamoto Y, Ning G al (2017) Iron addiction: a novel therapeutic target in ovarian cancer. Oncogene 36(29):4089–4099. https://doi.org/10.1038/onc.2017.11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Gaschler MM, Andia AA, Liu HR, Csuka JM, Hurlocker B, Vaiana CA et al (2018) FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol 14(5):507. https://doi.org/10.1038/s41589-018-0031-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Ye LF, Chaudhary KR, Zandkarimi F, Harken AD, Kinslow CJ, Upadhyayula PS et al (2020) Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers. ACS Chem Biol 15(2):469–484. https://doi.org/10.1021/acschembio.9b00939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Xu S, Min JX, Wang FD (2021) Ferroptosis: an emerging player in immune cells. Sci Bull 66(22):2257–2260. https://doi.org/10.1016/j.scib.2021.02.026

    Article  CAS  Google Scholar 

  224. Lim SA, Wei J, Nguyen TM, Shi H, Su W, Palacios G al (2021) Lipid signalling enforces functional specialization of Treg cells in tumours. Nature 591(7849):306–311. https://doi.org/10.1038/s41586-021-03235-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Liu X, Hartman CL, Li L, Albert CJ, Si F, Gao A et al (2021) Reprogramming lipid metabolism prevents effector T cell senescence and enhances tumor immunotherapy. Sci Transl Med. https://doi.org/10.1126/scitranslmed.aaz6314

    Article  PubMed  PubMed Central  Google Scholar 

  226. Basit F, van Oppen LM, Schockel L, Bossenbroek HM, van Emst-de Vries SE, Hermeling JC et al (2017) Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase leading to necroptosis and ferroptosis in melanoma cells. Cell Death Dis 8(3):e2716. https://doi.org/10.1038/cddis.2017.133

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The graphical abstracts were created with BioRender software (BioRender.com).−

Funding

This work was supported by the National Natural Science Foundation of China (81972479, U2004118 and 82072899), Natural Science Foundation of Guangdong province (2019A1515011100 and 2021A1515012576), Henan Natural Science Foundation (202300410359) and Henan Medical Research Program (SBGJ2020002081), Guangzhou High-Level Clinical Key Specialty Construction Project; Clinical Key Specialty Construction Project of Guangzhou Medical University (202005), the Innovation Project of Universities in Guangdong Province (No. 2021KTSCX026), Scientific and Technological Planning Project of Guangzhou City (No. 201904010038), Special project of South China Normal University for foreign exchange in Guangdong Hong Kong Macao Great Bay Area in 2022.

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  1. MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China

    Minhua Luo, Jiajing Yan, Xinyu Hu & Zhengzhi Zou

  2. Genetic and Prenatal Diagnosis Center, Department of Gynecology and Obstetrics, First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450052, China

    Haolong Li & Yibing Chen

  3. School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, 999077, China

    Haolong Li

  4. Department of Breast Surgery, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China

    Hongsheng Li

  5. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510631, China

    Quentin Liu

  6. Guangdong Provincial Key Laboratory of Laser Life Science, College of Biophotonics, South China Normal University, Guangzhou, 510631, China

    Zhengzhi Zou

  7. Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou, 510631, China

    Zhengzhi Zou

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ZZ and ML conceived the study and drafted de manuscript. JY, HL, HL and XH collected the related references. ZZ, YC and QL revised the manuscript. All authors read and approved the final manuscript.

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Luo, M., Yan, J., Hu, X. et al. Targeting lipid metabolism for ferroptotic cancer therapy. Apoptosis 28, 81–107 (2023). https://doi.org/10.1007/s10495-022-01795-0

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