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FSP1-mediated ferroptosis in cancer: from mechanisms to therapeutic applications

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Abstract 

Ferroptosis is a new discovered regulated cell death triggered by the ferrous ion (Fe2+)-dependent accumulation of lipid peroxides associated with cancer and many other diseases. The mechanism of ferroptosis includes oxidation systems (such as enzymatic oxidation and free radical oxidation) and antioxidant systems (such as GSH/GPX4, CoQ10/FSP1, BH4/GCH1 and VKORC1L1/VK). Among them, ferroptosis suppressor protein 1 (FSP1), as a crucial regulatory factor in the antioxidant system, has shown a crucial role in ferroptosis. FSP1 has been well validated to ferroptosis in three ways, and a variety of intracellular factors and drug molecules can alleviate ferroptosis via FSP1, which has been demonstrated to alter the sensitivity and effectiveness of cancer therapies, including chemotherapy, radiotherapy, targeted therapy and immunotherapy. This review aims to provide important frameworks that, bring the regulation of FSP1 mediated ferroptosis into cancer therapies on the basis of existing studies.

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Abbreviations

ACSL4:

Acyl-CoA synthetase long-chain family member 4

AEC2s:

Alveolar epithelial Type2 cells

AIFM2:

Apoptosis-inducing factor mitochondrial 2

ALL:

Acute lymphoblastic leukemia

ANXA7:

Annexin A7

AR:

Androgen receptor

BH4:

Tetrahydrobiopterin

BMP:

BODIPY-modified polyamide

CHMP5:

Charged multivesicular body protein 5

CHMP6:

Charged multivesicular body protein 6

CoQ10:

Ubiquinone-10

CoQ10H2:

Ubiquinol

CRPC:

Castration-resistant prostate cancer

CTRP:

Cancer Therapeutics Response Portal

CTD:

C-terminal domain

CYP2J2:

Cytochrome P450 2J2

DAMP:

Damage-associated molecular patterns

DHFR:

Dihydrofolate reductase

DHODH:

Dihydroorotate dehydrogenase

EMT:

Epithelial-mesenchymal transformation

ER:

Estrogen receptor

ESCC:

Esophageal squamous cell carcinoma

ETC:

Electronic transport chain

FSEN1:

Ferroptosis sensitizer Ferroptosis sensitizer 1

FSP1:

Ferroptosis suppressor protein 1

GCH1:

GTP cyclohydrolase-1

GPX4:

Glutathione peroxidase 4

GSH:

Glutathione

HA:

Hyaluronic acid

HCC:

Hepatocellular carcinoma

HMGB1:

High mobility group box 1

ICD:

Immunogenic cell death

IPP:

Isopentenyl pyrophosphate

IR:

Ionizing radiation

LPCAT3:

Lysophosphatidylcholine acyltransferase 3

LSCs:

Lung cancer stem cells

MDA:

Malondialdehyde

MOF:

Metal-organic framework

MK4:

Menaquinone-4

PDAC:

Pancreatic ductal adenocarcinoma

PDCD6IP:

Programmed cell death 6-interacting protein

PIE:

Propofol injectable emulsion

PLOOH:

Phospholipid hydroperoxide

PUFA:

Polyunsaturated fatty acid

PUFA-CoA:

Coenzyme A-activated polyunsaturated fatty acid

PUFA-PLs:

Polyunsaturated fatty acids phospholipids

Py-RSL:

Pyridine RAS-selective lethal ligand

QLD:

QiLing Decoction

RCD:

Regulated cell death

ROS:

Reactive oxygen species

RT:

Radiotherapy

RTA:

RTA Radical-trapping antioxidant

TME:

Tumor microenvironment

TSS:

Transcriptional start site

TSG101:

Tumor susceptibility 101

VKH2:

Vitamin K hydroquinone

VK:

Vitamin K

VKORC1L1:

Vitamin K epoxide reductase complex subunit 1 like 1

4HNE :

4-Hydroxynonenal

References  

  1. Galluzzi L et al (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25(3):486–541

    Article  PubMed  PubMed Central  Google Scholar 

  2. Dixon SJ et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149(5):1060–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Li FJ et al (2022) System X(c) (-)/GSH/GPX4 axis: An important antioxidant system for the ferroptosis in drug-resistant solid tumor therapy. Front Pharmacol 13:910292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Bersuker K et al (2019) The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575(7784):688–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hu Q et al (2022) Blockade of GCH1/BH4 Axis Activates Ferritinophagy to Mitigate the Resistance of Colorectal Cancer to Erastin-Induced Ferroptosis. Front Cell Dev Biol 10:810327

    Article  PubMed  PubMed Central  Google Scholar 

  6. Qiu B et al (2024) Phospholipids with two polyunsaturated fatty acyl tails promote ferroptosis. Cell 187(5):1177-1190.e18

    Article  CAS  PubMed  Google Scholar 

  7. Zhang F et al (2023) Current insights into the functional roles of ferroptosis in musculoskeletal diseases and therapeutic implications. Front Cell Dev Biol 11:1112751

    Article  PubMed  PubMed Central  Google Scholar 

  8. Magtanong L et al (2019) Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State. Cell Chem Biol 26(3):420-432.e9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Doll S et al (2017) ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 13(1):91–98

    Article  CAS  PubMed  Google Scholar 

  10. Cui J et al (2023) LPCAT3 Is Transcriptionally Regulated by YAP/ZEB/EP300 and Collaborates with ACSL4 and YAP to Determine Ferroptosis Sensitivity. Antioxid Redox Signal 39(7–9):491–511

    Article  CAS  PubMed  Google Scholar 

  11. Lee H et al (2020) Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat Cell Biol 22(2):225–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wang K et al (2021) Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells. Cell Death Differ 28(4):1222–1236

    Article  CAS  PubMed  Google Scholar 

  13. Jiang X, Stockwell BR, Conrad M (2021) Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 22(4):266–282

    Article  PubMed  PubMed Central  Google Scholar 

  14. 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

    Article  PubMed  PubMed Central  Google Scholar 

  15. Conrad M, Pratt DA (2019) The chemical basis of ferroptosis. Nat Chem Biol 15(12):1137–1147

    Article  CAS  PubMed  Google Scholar 

  16. Kagan VE et al (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13(1):81–90

    Article  CAS  PubMed  Google Scholar 

  17. Lee JY 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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liang D et al (2023) Ferroptosis surveillance independent of GPX4 and differentially regulated by sex hormones. Cell 186(13):2748-2764.e22

    Article  CAS  PubMed  Google Scholar 

  19. Dixon SJ, Stockwell BR (2014) The role of iron and reactive oxygen species in cell death. Nat Chem Biol 10(1):9–17

    Article  CAS  PubMed  Google Scholar 

  20. Doll S, Conrad M (2017) Iron and ferroptosis: A still ill-defined liaison. IUBMB Life 69(6):423–434

    Article  CAS  PubMed  Google Scholar 

  21. Shah R, Shchepinov MS, Pratt DA (2018) Resolving the Role of Lipoxygenases in the Initiation and Execution of Ferroptosis. ACS Cent Sci 4(3):387–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Aldrovandi M, Fedorova M, Conrad M (2021) Juggling with lipids, a game of Russian roulette. Trends Endocrinol Metab 32(7):463–473

    Article  CAS  PubMed  Google Scholar 

  23. Kagan VE et al (2020) Redox phospholipidomics of enzymatically generated oxygenated phospholipids as specific signals of programmed cell death. Free Radic Biol Med 147:231–241

    Article  CAS  PubMed  Google Scholar 

  24. Gao M et al (2015) Glutaminolysis and Transferrin Regulate Ferroptosis. Mol Cell 59(2):298–308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Tang D et al (2021) Ferroptosis: molecular mechanisms and health implications. Cell Res 31(2):107–125

    Article  CAS  PubMed  Google Scholar 

  26. Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417(1):1–13

    Article  CAS  PubMed  Google Scholar 

  27. Gao M et al (2019) Role of Mitochondria in Ferroptosis. Mol Cell 73(2):354-363.e3

    Article  CAS  PubMed  Google Scholar 

  28. Li C et al (2021) Mitochondrial DNA stress triggers autophagy-dependent ferroptotic death. Autophagy 17(4):948–960

    Article  CAS  PubMed  Google Scholar 

  29. Richardson DR et al (2010) Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol. Proc Natl Acad Sci U S A 107(24):10775–10782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nie G et al (2005) Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis. Blood 105(5):2161–2167

    Article  CAS  PubMed  Google Scholar 

  31. Paul BT et al (2017) Mitochondria and Iron: current questions. Expert Rev Hematol 10(1):65–79

    Article  CAS  PubMed  Google Scholar 

  32. Burdo J, Dargusch R, Schubert D (2006) Distribution of the cystine/glutamate antiporter system xc- in the brain, kidney, and duodenum. J Histochem Cytochem 54(5):549–557

    Article  CAS  PubMed  Google Scholar 

  33. Dixon SJ et al (2014) Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3:e02523

    Article  PubMed  PubMed Central  Google Scholar 

  34. Battaglia AM et al (2020) Ferroptosis and Cancer: Mitochondria Meet the “Iron Maiden” Cell Death. Cells 9(6):1505

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yang WS, Stockwell BR (2016) Ferroptosis: Death by Lipid Peroxidation. Trends Cell Biol 26(3):165–176

    Article  CAS  PubMed  Google Scholar 

  36. Friedmann Angeli JP et al (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16(12):1180–1191

    Article  CAS  PubMed  Google Scholar 

  37. Doll S et al (2019) FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575(7784):693–698

    Article  CAS  PubMed  Google Scholar 

  38. Kraft VAN et al (2020) GTP Cyclohydrolase 1/Tetrahydrobiopterin Counteract Ferroptosis through Lipid Remodeling. ACS Cent Sci 6(1):41–53

    Article  CAS  PubMed  Google Scholar 

  39. Soula M et al (2020) Metabolic determinants of cancer cell sensitivity to canonical ferroptosis inducers. Nat Chem Biol 16(12):1351–1360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mao C et al (2021) DHODH-mediated ferroptosis defence is a targetable vulnerability in cancer. Nature 593(7860):586–590

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang F, Min J (2021) DHODH tangoing with GPX4 on the ferroptotic stage. Signal Transduct Target Ther 6(1):244

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mishima E et al (2023) DHODH inhibitors sensitize to ferroptosis by FSP1 inhibition. Nature 619(7968):E9–E18

    Article  CAS  PubMed  Google Scholar 

  43. Mishima E et al (2022) A non-canonical vitamin K cycle is a potent ferroptosis suppressor. Nature 608(7924):778–783

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yang X et al (2023) Regulation of VKORC1L1 is critical for p53-mediated tumor suppression through vitamin K metabolism. Cell Metab 35(8):1474-1490.e8

    Article  CAS  PubMed  Google Scholar 

  45. Kolbrink B et al (2022) Vitamin K1 inhibits ferroptosis and counteracts a detrimental effect of phenprocoumon in experimental acute kidney injury. Cell Mol Life Sci 79(7):387

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jin DY et al (2023) A genome-wide CRISPR-Cas9 knockout screen identifies FSP1 as the warfarin-resistant vitamin K reductase. Nat Commun 14(1):828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wu M et al (2002) AMID, an apoptosis-inducing factor-homologous mitochondrion-associated protein, induces caspase-independent apoptosis. J Biol Chem 277(28):25617–25623

    Article  CAS  PubMed  Google Scholar 

  48. Ohiro Y et al (2002) A novel p53-inducible apoptogenic gene, PRG3, encodes a homologue of the apoptosis-inducing factor (AIF). FEBS Lett 524(1–3):163–171

    Article  CAS  PubMed  Google Scholar 

  49. Eisenhaber F et al (2003) Prediction of lipid posttranslational modifications and localization signals from protein sequences: big-Pi, NMT and PTS1. Nucleic Acids Res 31(13):3631–3634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Borgese N et al (1996) A role for N-myristoylation in protein targeting: NADH-cytochrome b5 reductase requires myristic acid for association with outer mitochondrial but not ER membranes. J Cell Biol 135(6):1501–1513

    Article  CAS  PubMed  Google Scholar 

  51. Maurer-Stroh S et al (2004) MYRbase: analysis of genome-wide glycine myristoylation enlarges the functional spectrum of eukaryotic myristoylated proteins. Genome Biol 5(3):R21

    Article  PubMed  PubMed Central  Google Scholar 

  52. Lv Y et al (2023) Structural insights into FSP1 catalysis and ferroptosis inhibition. Nat Commun 14(1):5933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Bai Y et al (2019) Lipid storage and lipophagy regulates ferroptosis. Biochem Biophys Res Commun 508(4):997–1003

    Article  CAS  PubMed  Google Scholar 

  54. Zhu S et al (2017) HSPA5 Regulates Ferroptotic Cell Death in Cancer Cells. Cancer Res 77(8):2064–2077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Dai E et al (2020) AIFM2 blocks ferroptosis independent of ubiquinol metabolism. Biochem Biophys Res Commun 523(4):966–971

    Article  CAS  PubMed  Google Scholar 

  56. Nguyen TB et al (2017) DGAT1-Dependent Lipid Droplet Biogenesis Protects Mitochondrial Function during Starvation-Induced Autophagy. Dev Cell 42(1):9-21.e5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Arroyo A et al (1998) Ubiquinol regeneration by plasma membrane ubiquinone reductase. Protoplasma 205(1):107–113

    Article  CAS  Google Scholar 

  58. Crane FL (2007) Discovery of ubiquinone (coenzyme Q) and an overview of function. Mitochondrion 7(Suppl):S2-7

    Article  CAS  PubMed  Google Scholar 

  59. Bentinger M, Brismar K, Dallner G (2007) The antioxidant role of coenzyme Q. Mitochondrion 7(Suppl):S41-50

    Article  CAS  PubMed  Google Scholar 

  60. Hadian K (2020) Ferroptosis Suppressor Protein 1 (FSP1) and Coenzyme Q(10) Cooperatively Suppress Ferroptosis. Biochemistry 59(5):637–638

    Article  CAS  PubMed  Google Scholar 

  61. Koppula P et al (2022) A targetable CoQ-FSP1 axis drives ferroptosis- and radiation-resistance in KEAP1 inactive lung cancers. Nat Commun 13(1):2206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kim JW et al (2023) FSP1 confers ferroptosis resistance in KEAP1 mutant non-small cell lung carcinoma in NRF2-dependent and -independent manner. Cell Death Dis 14(8):567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Mukai K, Itoh S, Morimoto H (1992) Stopped-flow kinetic study of vitamin E regeneration reaction with biological hydroquinones (reduced forms of ubiquinone, vitamin K, and tocopherolquinone) in solution. J Biol Chem 267(31):22277–22281

    Article  CAS  PubMed  Google Scholar 

  64. Pedrera L et al (2021) Ferroptotic pores induce Ca(2+) fluxes and ESCRT-III activation to modulate cell death kinetics. Cell Death Differ 28(5):1644–1657

    Article  CAS  PubMed  Google Scholar 

  65. Espiritu RA, Pedrera L, Ros U (2019) Tuning the way to die: implications of membrane perturbations in necroptosis. In: IgliÊ A, Garcia-Sáez A, Rappolt M (eds) Advances in biomembranes and lipid self- assembly. Cambridge, Massachusetts: Academic Press.

  66. Jimenez AJ et al (2014) ESCRT Machinery Is Required for Plasma Membrane Repair. Science 343(6174):1247136

    Article  PubMed  Google Scholar 

  67. Gong YN et al (2017) ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences. Cell 169(2):286-300.e16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gong YN et al (2017) Biological events and molecular signaling following MLKL activation during necroptosis. Cell Cycle 16(19):1748–1760

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Rühl S et al (2018) ESCRT-dependent membrane repair negatively regulates pyroptosis downstream of GSDMD activation. Science 362(6417):956–960

    Article  PubMed  Google Scholar 

  70. Sonder SL et al (2019) Annexin A7 is required for ESCRT III-mediated plasma membrane repair. Sci Rep 9(1):6726

    Article  PubMed  PubMed Central  Google Scholar 

  71. Morita E et al (2007) Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis. EMBO J 26(19):4215–4227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Scheffer LL et al (2014) Mechanism of Ca(2)(+)-triggered ESCRT assembly and regulation of cell membrane repair. Nat Commun 5:5646

    Article  CAS  PubMed  Google Scholar 

  73. Dai E et al (2020) ESCRT-III-dependent membrane repair blocks ferroptosis. Biochem Biophys Res Commun 522(2):415–421

    Article  CAS  PubMed  Google Scholar 

  74. Yang Z et al (2023) HIF-1alpha drives resistance to ferroptosis in solid tumors by promoting lactate production and activating SLC1A1. Cell Rep 42(8):112945

    Article  CAS  PubMed  Google Scholar 

  75. Pontel LB et al (2022) Acute lymphoblastic leukemia necessitates GSH-dependent ferroptosis defenses to overcome FSP1-epigenetic silencing. Redox Biol 55:102408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Liu Y et al (2022) UHRF1-mediated ferroptosis promotes pulmonary fibrosis via epigenetic repression of GPX4 and FSP1 genes. Cell Death Dis 13(12):1070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Muller F et al (2023) Elevated FSP1 protects KRAS-mutated cells from ferroptosis during tumor initiation. Cell Death Differ 30(2):442–456

    Article  PubMed  Google Scholar 

  78. Donati B, Lorenzini E, Ciarrocchi A (2018) BRD4 and Cancer: going beyond transcriptional regulation. Mol Cancer 17(1):164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Schmitt A et al (2023) BRD4 inhibition sensitizes diffuse large B-cell lymphoma cells to ferroptosis. Blood 142(13):1143–1155

    Article  CAS  PubMed  Google Scholar 

  80. Ebrahimi SO, Reiisi S (2019) Downregulation of miR-4443 and miR-5195-3p in ovarian cancer tissue contributes to metastasis and tumorigenesis. Arch Gynecol Obstet 299(5):1453–1458

    Article  CAS  PubMed  Google Scholar 

  81. Song Z et al (2021) Exosomal miR-4443 promotes cisplatin resistance in non-small cell lung carcinoma by regulating FSP1 m6A modification-mediated ferroptosis. Life Sci 276:119399

    Article  CAS  PubMed  Google Scholar 

  82. Li M et al (2020) Long Noncoding RNA LINC00460 Promotes Cell Progression by Sponging miR-4443 in Head and Neck Squamous Cell Carcinoma. Cell Transplant 29:963689720927405

    Article  PubMed  Google Scholar 

  83. Gao Y et al (2019) lncRNA MNX1-AS1 Promotes Glioblastoma Progression Through Inhibition of miR-4443. Oncol Res 27(3):341–347

    Article  PubMed  PubMed Central  Google Scholar 

  84. Gridelli C et al (2018) Cisplatin-Based First-Line Treatment of Elderly Patients With Advanced Non-Small-Cell Lung Cancer: Joint Analysis of MILES-3 and MILES-4 Phase III Trials. J Clin Oncol 36(25):2585–2592

    Article  CAS  PubMed  Google Scholar 

  85. Guo J et al (2018) Ferroptosis: A Novel Anti-tumor Action for Cisplatin. Cancer Res Treat 50(2):445–460

    Article  CAS  PubMed  Google Scholar 

  86. Griesinger F et al (2019) Efficacy and safety of first-line carboplatin-versus cisplatin-based chemotherapy for non-small cell lung cancer: A meta-analysis. Lung Cancer 135:196–204

    Article  PubMed  Google Scholar 

  87. Zappa C, Mousa SA (2016) Non-small cell lung cancer: current treatment and future advances. Transl Lung Cancer Res 5(3):288–300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. MacDonagh L et al (2018) BBI608 inhibits cancer stemness and reverses cisplatin resistance in NSCLC. Cancer Lett 428:117–126

    Article  CAS  PubMed  Google Scholar 

  89. Montgomery DC et al (2016) Global Profiling of Acetyltransferase Feedback Regulation. J Am Chem Soc 138(20):6388–6391

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Sharma S et al (2015) Yeast Kre33 and human NAT10 are conserved 18S rRNA cytosine acetyltransferases that modify tRNAs assisted by the adaptor Tan1/THUMPD1. Nucleic Acids Res 43(4):2242–2258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Tsai K et al (2020) Acetylation of cytidine residues boosts HIV-1 gene expression by increasing viral RNA stability. Cell Host Microbe 28(2):306–312.e6

  92. Zheng X et al (2022) N-acetyltransferase 10 promotes colon cancer progression by inhibiting ferroptosis through N4-acetylation and stabilization of ferroptosis suppressor protein 1 (FSP1) mRNA. Cancer Commun (Lond) 42(12):1347–1366

    Article  PubMed  Google Scholar 

  93. Dalhat MH et al (2021) Remodelin, a N-acetyltransferase 10 (NAT10) inhibitor, alters mitochondrial lipid metabolism in cancer cells. J Cell Biochem 122(12):1936–1945

  94. Sas-Chen A et al (2020) Dynamic RNA acetylation revealed by quantitative cross-evolutionary mapping. Nature 583(7817):638–643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Balmus G et al (2018) Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome. Nat Commun 9(1):1700

    Article  PubMed  PubMed Central  Google Scholar 

  96. Bazhabayi M et al (2021) CircGFRA1 facilitates the malignant progression of HER-2-positive breast cancer via acting as a sponge of miR-1228 and enhancing AIFM2 expression. J Cell Mol Med 25(21):10248–10256

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhang Y et al (2022) The microRNA-3622 family at the 8p21 locus exerts oncogenic effects by regulating the p53-downstream gene network in prostate cancer progression. Oncogene 41(23):3186–3196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Wang Y (2017) The inhibition of microRNA-15a suppresses hepatitis B virus-associated liver cancer cell growth through the Smad/TGF-beta pathway. Oncol Rep 37(6):3520–3526

    Article  CAS  PubMed  Google Scholar 

  99. Liu MR et al (2023) Sorafenib induces ferroptosis by promoting TRIM54-mediated FSP1 ubiquitination and degradation in hepatocellular carcinoma. Hepatol Commun 7(10):e0246

    Article  PubMed  PubMed Central  Google Scholar 

  100. Yuan J et al (2022) HDLBP-stabilized lncFAL inhibits ferroptosis vulnerability by diminishing Trim69-dependent FSP1 degradation in hepatocellular carcinoma. Redox Biol 58:102546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Gong J et al (2023) TRIM21-Promoted FSP1 Plasma Membrane Translocation Confers Ferroptosis Resistance in Human Cancers. Adv Sci (Weinh) 10:e2302318

    Article  PubMed  Google Scholar 

  102. Nakamura T et al (2023) Phase separation of FSP1 promotes ferroptosis. Nature 619(7969):371–377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Zhang Q et al (2023) ACSL1-induced ferroptosis and platinum resistance in ovarian cancer by increasing FSP1 N-myristylation and stability. Cell Death Discov 9(1):83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Tao P et al (2021) CYP2J2-produced epoxyeicosatrienoic acids contribute to the ferroptosis resistance of pancreatic ductal adenocarcinoma in a PPARgamma-dependent manner. Zhong Nan Da Xue Xue Bao Yi Xue Ban 46(9):932–941

    PubMed  Google Scholar 

  105. Efimova I et al (2020) Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity. J Immunother Cancer 8(2)

  106. Ma J et al (2023) Composite Hydrogel for Spatiotemporal Lipid Intervention of Tumor Milieu. Adv Mater 35(14):e2211579

    Article  PubMed  Google Scholar 

  107. Luo X et al (2021) Oxygenated phosphatidylethanolamine navigates phagocytosis of ferroptotic cells by interacting with TLR2. Cell Death Differ 28(6):1971–1989

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Kim KS et al (2022) Enhanced natural killer cell anti-tumor activity with nanoparticles mediated ferroptosis and potential therapeutic application in prostate cancer. J Nanobiotechnol 20(1):428

    Article  CAS  Google Scholar 

  109. Zhang H et al (2022) Dihydroartemisinin inhibits the growth of pancreatic cells by inducing ferroptosis and activating antitumor immunity. Eur J Pharmacol 926:175028

    Article  CAS  PubMed  Google Scholar 

  110. Wiernicki B et al (2022) Cancer cells dying from ferroptosis impede dendritic cell-mediated anti-tumor immunity. Nat Commun 13(1):3676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Mbah NE, Lyssiotis CA (2022) Metabolic regulation of ferroptosis in the tumor microenvironment. J Biol Chem 298(3):101617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Hayes JD, Dinkova-Kostova AT, Tew KD (2020) Oxidative Stress in Cancer. Cancer Cell 38(2):167–197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Spranger S et al (2017) Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell 31(5):711-723.e4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Conche C et al (2023) Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade. Gut 72(9):1774–1782

    Article  CAS  PubMed  Google Scholar 

  115. Zang J et al (2023) Overexpression of ferroptosis-related genes FSP1 and CISD1 is related to prognosis and tumor immune infiltration in gastric cancer. Clin Transl Oncol 25(8):2532–2544

    Article  CAS  PubMed  Google Scholar 

  116. Cheu JW et al (2023) Ferroptosis Suppressor Protein 1 Inhibition Promotes Tumor Ferroptosis and Anti-tumor Immune Responses in Liver Cancer. Cell Mol Gastroenterol Hepatol 16(1):133–159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Drijvers JM et al (2021) Pharmacologic Screening Identifies Metabolic Vulnerabilities of CD8(+) T Cells. Cancer Immunol Res 9(2):184–199

    Article  CAS  PubMed  Google Scholar 

  118. Xavier da Silva TN et al (2023) Molecular characterization of AIFM2/FSP1 inhibition by iFSP1-like molecules. Cell Death Dis 14(4):281

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Cheu JW et al (2023) Ferroptosis suppressor protein 1 inhibition promotes tumor ferroptosis and anti-tumor immune responses in liver cancer. Cell Mol Gastroenterol Hepatol 16(1):133–159

  120. Ozga AJ, Chow MT, Luster AD (2021) Chemokines and the immune response to cancer. Immunity 54(5):859–874

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. House IG et al (2020) Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade. Clin Cancer Res 26(2):487–504

    Article  CAS  PubMed  Google Scholar 

  122. Truman LA et al (2008) CX3CL1/fractalkine is released from apoptotic lymphocytes to stimulate macrophage chemotaxis. Blood 112(13):5026–5036

    Article  CAS  PubMed  Google Scholar 

  123. Yamasaki M et al (2010) p53 genotype predicts response to chemotherapy in patients with squamous cell carcinoma of the esophagus. Ann Surg Oncol 17(2):634–642

    Article  PubMed  Google Scholar 

  124. Miyauchi W et al (2022) Simultaneous regulation of ferroptosis suppressor protein 1 and glutathione peroxidase 4 as a new therapeutic strategy of ferroptosis for esophageal squamous cell carcinoma. Esophagus-Tokyo 20(3):492–501

  125. Qiu C et al (2022) Novel Therapeutic Savior for Osteosarcoma: The Endorsement of Ferroptosis. Front Oncol 12:746030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Nakamura T et al (2023) Integrated chemical and genetic screens unveil FSP1 mechanisms of ferroptosis regulation. Nat Struct Mol Biol 30(11):1806–1815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Hendricks JM et al (2023) Identification of structurally diverse FSP1 inhibitors that sensitize cancer cells to ferroptosis. Cell Chem Biol 30(9):1090-1103.e7

    Article  CAS  PubMed  Google Scholar 

  128. Yoshioka H et al (2022) Identification of a Small Molecule That Enhances Ferroptosis via Inhibition of Ferroptosis Suppressor Protein 1 (FSP1). ACS Chem Biol 17(2):483–491

    Article  CAS  PubMed  Google Scholar 

  129. Zhao X et al (2023) A chiral fluorescent Ir(iii) complex that targets the GPX4 and ErbB pathways to induce cellular ferroptosis. Chem Sci 14(5):1114–1122

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Cao H et al (2023) QiLing Decoction promotes ferroptosis of castration-resistant prostate cancer cells by inhibiting FSP1 in vitro and in vivo. J Cancer 14(12):2236–2245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Chen X et al (2022) Ferroptosis Induction Improves the Sensitivity of Docetaxel in Prostate Cancer. Oxid Med Cell Longev 2022:1–16

    Google Scholar 

  132. Zhou J et al (2023) Curcumin Induces Ferroptosis in A549 CD133(+) Cells through the GSH-GPX4 and FSP1-CoQ10-NAPH Pathways. Discov Med 35(176):251–263

    Article  PubMed  Google Scholar 

  133. Wan MohdTajuddin WNB et al (2019) Mechanistic Understanding of Curcumin’s Therapeutic Effects in Lung Cancer. Nutrients 11(12):2989

    Article  Google Scholar 

  134. Miyazaki K et al (2023) Curcumin and Andrographis Exhibit Anti-Tumor Effects in Colorectal Cancer via Activation of Ferroptosis and Dual Suppression of Glutathione Peroxidase-4 and Ferroptosis Suppressor Protein-1. Pharmaceuticals (Basel) 16(3):383

    Article  CAS  PubMed  Google Scholar 

  135. Sessler DI, Riedel B (2019) Anesthesia and Cancer Recurrence: Context for Divergent Study Outcomes. Anesthesiology 130(1):3–5

    Article  PubMed  Google Scholar 

  136. Zhao MY et al (2022) Propofol Augments Paclitaxel-Induced Cervical Cancer Cell Ferroptosis In Vitro. Front Pharmacol 13:816432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Utsumi T et al (2018) Identification and characterization of protein N-myristoylation occurring on four human mitochondrial proteins, SAMM50, TOMM40, MIC19, and MIC25. PLoS ONE 13(11):e0206355

    Article  PubMed  PubMed Central  Google Scholar 

  138. Fedoryshchak RO et al (2023) Discovery of lipid-mediated protein-protein interactions in living cells using metabolic labeling with photoactivatable clickable probes. Chem Sci 14(9):2419–2430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Li K et al (2022) Multienzyme-like Reactivity Cooperatively Impairs Glutathione Peroxidase 4 and Ferroptosis Suppressor Protein 1 Pathways in Triple-Negative Breast Cancer for Sensitized Ferroptosis Therapy. ACS nano 16(2):2381–2398

    Article  CAS  PubMed  Google Scholar 

  140. Zhu P, Chen Y, Shi J (2018) Nanoenzyme-Augmented Cancer Sonodynamic Therapy by Catalytic Tumor Oxygenation. ACS Nano 12(4):3780–3795

    Article  CAS  PubMed  Google Scholar 

  141. Zeng Z et al (2021) Activatable Polymer Nanoenzymes for Photodynamic Immunometabolic Cancer Therapy. Adv Mater 33(4):e2007247

    Article  PubMed  Google Scholar 

  142. Yu Z et al (2020) Nanoenzymes in disease diagnosis and therapy. Chem Commun (Camb) 56(99):15513–15524

    Article  CAS  PubMed  Google Scholar 

  143. Yang J et al (2022) Metabolic Intervention Nanoparticles for Triple-Negative Breast Cancer Therapy via Overcoming FSP1-Mediated Ferroptosis Resistance. Adv Healthc Mater 11(13):e2102799

    Article  PubMed  Google Scholar 

  144. Stockwell BR, Jiang X (2020) The Chemistry and Biology of Ferroptosis. Cell Chem Biol 27(4):365–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Beckwitt CH et al (2018) Statins attenuate outgrowth of breast cancer metastases. Br J Cancer 119(9):1094–1105

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Fromigue O, Hamidouche Z, Marie PJ (2008) Blockade of the RhoA-JNK-c-Jun-MMP2 cascade by atorvastatin reduces osteosarcoma cell invasion. J Biol Chem 283(45):30549–30556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Tan M et al (2019) Silk Fibroin-Coated Nanoagents for Acidic Lysosome Targeting by a Functional Preservation Strategy in Cancer Chemotherapy. Theranostics 9(4):961–973

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Delaney G et al (2005) The role of radiotherapy in cancer treatment: estimating optimal utilization from a review of evidence-based clinical guidelines. Cancer 104(6):1129–1137

    Article  PubMed  Google Scholar 

  149. Azzam EI, Jay-Gerin JP, Pain D (2012) Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury. Cancer Lett 327(1–2):48–60

    Article  CAS  PubMed  Google Scholar 

  150. Reisz JA et al (2014) Effects of ionizing radiation on biological molecules–mechanisms of damage and emerging methods of detection. Antioxid Redox Signal 21(2):260–292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Baidoo KE, Yong K, Brechbiel MW (2013) Molecular pathways: targeted alpha-particle radiation therapy. Clin Cancer Res 19(3):530–537

    Article  CAS  PubMed  Google Scholar 

  152. Adjemian S et al (2020) Ionizing radiation results in a mixture of cellular outcomes including mitotic catastrophe, senescence, methuosis, and iron-dependent cell death. Cell Death Dis 11(11):1003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Lei G et al (2021) Ferroptosis, radiotherapy, and combination therapeutic strategies. Protein Cell 12(11):836–857

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Venkatesh D et al (2020) MDM2 and MDMX promote ferroptosis by PPARalpha-mediated lipid remodeling. Genes Dev 34(7–8):526–543

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Zou Y, Schreiber SL (2020) Progress in Understanding Ferroptosis and Challenges in Its Targeting for Therapeutic Benefit. Cell Chem Biol 27(4):463–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Tang W et al (2020) The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduct Target Ther 5(1):87

    Article  PubMed  PubMed Central  Google Scholar 

  157. Zhao L et al (2022) Ferroptosis in cancer and cancer immunotherapy. Cancer Commun (Lond) 42(2):88–116

    Article  PubMed  PubMed Central  Google Scholar 

  158. Zhou Y et al (2023) A green light-enhanced cytosolic protein delivery platform based on BODIPY-protein interactions. Nano Res 16(1):1042–1051

    Article  CAS  Google Scholar 

  159. Zhou Y et al (2023) Photo-Enhanced Synergistic Induction of Ferroptosis for Anti-Cancer Immunotherapy. Adv Healthc Mater 12:e2300994

    Article  PubMed  Google Scholar 

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Funding

This work was supported by the National Natural Science Foundation of China (Grant No. 82303270), the Excellent Young Medical Talents Training Fund of the First Affiliated Hospital of Harbin Medical University (Grant No. 2021Y06), Heilongjiang Postdoctoral Scientific Research Developmental Fund (Grant No. LBH-Q18089), the University Nursing Program for Young Scholars with Creative Talents in Heilongjiang Province (Grant No. UNPYSCT-2018070), Chen Xiao-Ping Foundation For The Development Of Science And Technology Of Hubei Province (Grant No. CXPJJH121001-2021029).

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  1. Ran Gao and Jinge Wang contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, the First Affiliated Hospital of Harbin Medical University, Harbin, China

    Ran Gao, Jingjing Huang, Tong Wang, Lingfeng Guo, Wenlu Liu, Jialu Guan, Desen Liang, Qinghui Meng & Huayang Pan

  2. Department of General Surgery, the First Affiliated Hospital of Harbin Medical University, Harbin, China

    Ran Gao, Jingjing Huang, Tong Wang, Lingfeng Guo, Wenlu Liu, Jialu Guan, Desen Liang, Qinghui Meng & Huayang Pan

  3. School of Public Health, Harbin Medical University, Harbin, China

    Jinge Wang

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  1. Ran Gao
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Contributions

RG and JGW conceived and drafted the manuscript, drew the figures, and summarized the tables. JJH, TW, LFG, WLL, and JLG discussed the concepts of the manuscript. DSL, QHM and HYP provided valuable suggestion. HYP approved the submission of the manuscript RG and JGW contributed equally to this work.

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Correspondence to Huayang Pan.

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Gao, R., Wang, J., Huang, J. et al. FSP1-mediated ferroptosis in cancer: from mechanisms to therapeutic applications. Apoptosis (2024). https://doi.org/10.1007/s10495-024-01966-1

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