Skip to main content

Advertisement

SpringerLink
Log in

Targeting ferroptosis in hepatocellular carcinoma

  • Review Article
  • Published:
Hepatology International Aims and scope Submit manuscript

A Correction to this article was published on 21 December 2023

This article has been updated

Abstract

Hepatocellular carcinoma (HCC) is a common malignant tumor with complex survival mechanism and drug resistance, resulting in cancer-related high mortality in the world. Ferroptosis represents a form of regulated cell death, typically distinguished by iron-dependent lipid peroxidation. Cancer cells often employ antioxidant defenses to evade the harmful effects of excess iron. Recent research has proposed that directing interventions towards ferroptosis could serve as an effective strategy in curbing the proliferation and invasion of HCC. Immunotherapy has made some preliminary progress in the remodeling of immune microenvironment, but it has not completely inhibited HCC growth, invasion and drug resistance. Furthermore, ferroptosis is widely observed in the formation of immune microenvironment of HCC and mediates the response of many targeted drugs and immunotherapy. Clarifying the role of ferroptosis in these complex processes is expected to provide a new prospect for HCC treatment. In this review, we outline the mechanisms by which HCC develops invasiveness and drug resistance by evading iron-dependent death, and paint a comprehensive landscape of ferroptosis in different cell types in the HCC immune microenvironment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Availability of data and materials

Not applicable.

Change history

Abbreviations

HCC:

Hepatocellular carcinoma

TACE:

Transcatheter arterial chemoembolization

HAIC:

Hepatic artery infusion chemotherapy

ROS:

Reactive oxygen species

PD-L1:

Programmed death-ligand 1

EGFR:

Epidermal growth factor receptor

TF:

Transferrin

STEAP3:

Six-transmembrane epithelial antigen of the prostate 3

LIP:

Labile iron pool

DMT1:

Divalent mental transporter 1

ZIP14:

Zinc–iron regulatory protein family 14

PRNP:

Prion protein

FPN:

Ferroportin

HO-1:

Heme oxygenase-1

FTH1:

Ferritin Heavy Chain 1

HSPB1:

Heat shock protein beta-1

PUFAs:

Polyunsaturated fatty acids

PE:

Phosphatidylethanolamine

ACSL4:

Acyl-coa synthetase long-chain family members 4

LPCAT3:

Lysophosphatidylcholine acyltransferase 3

GPXs:

Glutathione peroxidases

GSH:

Glutathione

GSSG:

Oxidized glutathione

RBP:

RNA binding protein

IRP1:

Iron regulatory protein 1

CNOT6:

CCR4–NOT Transcription Complex Subunit 6

MVE:

Mevalonote

FSP1:

Ferroptosis suppressor protein 1

DHODH:

Dihydroorotate dehydrogenase

GCH1:

GTP cyclohydrolase1

BH4 :

Tetrahydrobiopterin

PHGDH:

Phosphoglycerate dehydrogenase

DHA:

Dihydroartemisinin

SOCS2:

Suppressor of cytokine signaling 2

PPP:

Pentose phosphate pathway

ICI:

Immune checkpoint inhibitor

AA:

Arachidonic acid

OxLDL:

Oxidized low-density lipoprotein

TCR:

T-cell receptor

TAMs:

Tumor-associated macrophages

MDSCs:

Myeloid-derived suppressor cells

VEGF:

Vascular endothelial growth factor

PMNS:

Pathologically activated neutrophils

PMN–MDSCs:

Polymorphonuclear-Myeloid-derived suppressor cells

NK cells:

Natural killer cells

DCs:

Dendritic cells

CQDs:

Carbon Quantum Dots

References

  1. Sung H, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249

    Article  PubMed  Google Scholar 

  2. Siegel RL, et al. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7–33

    Article  PubMed  Google Scholar 

  3. Pinna AD, et al. Liver transplantation and hepatic resection can achieve cure for hepatocellular carcinoma. Ann Surg. 2018;268(5):868–875

    Article  PubMed  Google Scholar 

  4. Wang K, et al. Combination of ablation and immunotherapy for hepatocellular carcinoma: where we are and where to go. Front Immunol. 2021;12: 792781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Zheng J, et al. Actual 10-year survivors after resection of hepatocellular carcinoma. Ann Surg Oncol. 2017;24(5):1358–1366

    Article  PubMed  Google Scholar 

  6. Bodzin AS, et al. Predicting mortality in patients developing recurrent hepatocellular carcinoma after liver transplantation: impact of treatment modality and recurrence characteristics. Ann Surg. 2017;266(1):118–125

    Article  PubMed  Google Scholar 

  7. Shimizu R, et al. Feeding artery ablation before radiofrequency ablation for hepatocellular carcinoma may reduce critical recurrence. JGH Open. 2021;5(4):478–485

    Article  PubMed  PubMed Central  Google Scholar 

  8. Raoul JL, et al. Updated use of TACE for hepatocellular carcinoma treatment: How and when to use it based on clinical evidence. Cancer Treat Rev. 2019;72:28–36

    Article  CAS  PubMed  Google Scholar 

  9. Li QJ, et al. Hepatic arterial infusion of oxaliplatin, fluorouracil, and leucovorin versus transarterial chemoembolization for large hepatocellular carcinoma: a randomized phase III trial. J Clin Oncol. 2022;40(2):150–160

    Article  CAS  PubMed  Google Scholar 

  10. Jin Q, Chen X, Zheng S. The security rating on local ablation and interventional therapy for hepatocellular carcinoma (HCC) and the comparison among multiple anesthesia methods. Anal Cell Pathol (Amst). 2019;2019:2965173

    PubMed  Google Scholar 

  11. Xu J, et al. Anti-PD-1 antibody SHR-1210 combined with apatinib for advanced hepatocellular carcinoma, gastric, or esophagogastric junction cancer: an open-label, dose escalation and expansion study. Clin Cancer Res. 2019;25(2):515–523

    Article  CAS  PubMed  Google Scholar 

  12. Finn RS, et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N Engl J Med. 2020;382(20):1894–1905

    Article  CAS  PubMed  Google Scholar 

  13. Oura K, et al. Tumor immune microenvironment and immunosuppressive therapy in hepatocellular carcinoma: a review. Int J Mol Sci. 2021;22:11

    Article  Google Scholar 

  14. Fu Y, et al. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Cancer Res. 2019;38(1):396

    Article  PubMed  PubMed Central  Google Scholar 

  15. Zheng C, et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell. 2017;169(7):1342–1356

    Article  CAS  PubMed  Google Scholar 

  16. Abbott M, Ustoyev Y. Cancer and the immune system: the history and background of immunotherapy. Semin Oncol Nurs. 2019;35(5): 150923

    Article  PubMed  Google Scholar 

  17. Velcheti V, Schalper K. Basic overview of current immunotherapy approaches in cancer. Am Soc Clin Oncol Educ Book. 2016;35:298–308

    Article  PubMed  Google Scholar 

  18. Yap TA, et al. Development of immunotherapy combination strategies in cancer. Cancer Discov. 2021;11(6):1368–1397

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang T, et al. Comprehensive molecular analyses of a macrophage-related gene signature with regard to prognosis, immune features, and biomarkers for immunotherapy in hepatocellular carcinoma based on WGCNA and the LASSO algorithm. Front Immunol. 2022;13: 843408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Nat Rev Clin Oncol. 2020;17(7):395–417

    Article  PubMed  PubMed Central  Google Scholar 

  21. Yu T, et al. MT1JP-mediated miR-24-3p/BCL2L2 axis promotes Lenvatinib resistance in hepatocellular carcinoma cells by inhibiting apoptosis. Cell Oncol (Dordr). 2021;44(4):821–834

    Article  CAS  PubMed  Google Scholar 

  22. Yang JR, Ling XL, Guan QL. RAP2A promotes apoptosis resistance of hepatocellular carcinoma cells via the mTOR pathway. Clin Exp Med. 2021;21(4):545–554

    Article  CAS  PubMed  Google Scholar 

  23. Wang Q, et al. COX-2 induces apoptosis-resistance in hepatocellular carcinoma cells via the HIF-1alpha/PKM2 pathway. Int J Mol Med. 2019;43(1):475–488

    PubMed  Google Scholar 

  24. Yang T, et al. Selenium sulfide disrupts the PLAGL2/C-MET/STAT3-induced resistance against mitochondrial apoptosis in hepatocellular carcinoma. Clin Transl Med. 2021;11(9): e536

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li J, et al. Ferroptosis: past, present and future. Cell Death Dis. 2020;11(2):88

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ursini F, Maiorino M. Lipid peroxidation and ferroptosis: the role of GSH and GPx4. Free Radic Biol Med. 2020;152:175–185

    Article  CAS  PubMed  Google Scholar 

  28. Chen X, et al. Ferroptosis: machinery and regulation. Autophagy. 2021;17(9):2054–2081

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  29. Liang D, Minikes AM, Jiang X. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell. 2022;82(12):2215–2227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li Y, et al. Erastin induces ferroptosis via ferroportin-mediated iron accumulation in endometriosis. Hum Reprod. 2021;36(4):951–964

    Article  CAS  PubMed  Google Scholar 

  31. Chen X, et al. Ferroptosis and cardiovascular disease: role of free radical-induced lipid peroxidation. Free Radic Res. 2021;55(4):405–415

    Article  CAS  PubMed  Google Scholar 

  32. Lee JY, et al. Polyunsaturated fatty acid biosynthesis pathway determines ferroptosis sensitivity in gastric cancer. Proc Natl Acad Sci U S A. 2020;117(51):32433–32442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhang HL, et al. PKCbetaII phosphorylates ACSL4 to amplify lipid peroxidation to induce ferroptosis. Nat Cell Biol. 2022;24(1):88–98

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  34. Chen X, et al. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol. 2021;18(5):280–296

    Article  CAS  PubMed  Google Scholar 

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

    Article  MathSciNet  PubMed  PubMed Central  Google Scholar 

  36. Chen Y, et al. CRISPR screens uncover protective effect of PSTK as a regulator of chemotherapy-induced ferroptosis in hepatocellular carcinoma. Mol Cancer. 2022;21(1):11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Lal A. Iron in health and disease: an update. Indian J Pediatr. 2020;87(1):58–65

    Article  PubMed  Google Scholar 

  39. Shang Y, et al. Ceruloplasmin suppresses ferroptosis by regulating iron homeostasis in hepatocellular carcinoma cells. Cell Signal. 2020;72: 109633

    Article  CAS  PubMed  Google Scholar 

  40. Liuzzi JP, et al. Zip14 (Slc39a14) mediates non-transferrin-bound iron uptake into cells. Proc Natl Acad Sci U S A. 2006;103(37):13612–13617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pinilla-Tenas JJ, et al. Zip14 is a complex broad-scope metal-ion transporter whose functional properties support roles in the cellular uptake of zinc and nontransferrin-bound iron. Am J Physiol Cell Physiol. 2011;301(4):C862–C871

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tripathi AK, et al. Prion protein functions as a ferrireductase partner for ZIP14 and DMT1. Free Radic Biol Med. 2015;84:322–330

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Kwon MY, et al. Heme oxygenase-1 accelerates erastin-induced ferroptotic cell death. Oncotarget. 2015;6(27):24393–24403

    Article  PubMed  PubMed Central  Google Scholar 

  44. Wu A, et al. Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis. Redox Biol. 2021;46: 102131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Park E, Chung SW. ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation. Cell Death Dis. 2019;10(11):822

    Article  PubMed  PubMed Central  Google Scholar 

  46. Fang X, et al. Ferroptosis as a target for protection against cardiomyopathy. Proc Natl Acad Sci U S A. 2019;116(7):2672–2680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gammella E, et al. Iron-induced damage in cardiomyopathy: oxidative-dependent and independent mechanisms. Oxid Med Cell Longev. 2015;2015: 230182

    Article  PubMed  PubMed Central  Google Scholar 

  48. Ulrich DL, et al. ATP-dependent mitochondrial porphyrin importer ABCB6 protects against phenylhydrazine toxicity. J Biol Chem. 2012;287(16):12679–12690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Krishnamurthy P, Xie T, Schuetz JD. The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol Ther. 2007;114(3):345–358

    Article  CAS  PubMed  Google Scholar 

  50. Sun X, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene. 2015;34(45):5617–5625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Yanatori I, et al. Chaperone protein involved in transmembrane transport of iron. Biochem J. 2014;462(1):25–37

    Article  CAS  PubMed  Google Scholar 

  52. Chen D, et al. NRF2 is a major target of ARF in p53-independent tumor suppression. Mol Cell. 2017;68(1):224–232

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Chen D, et al. ATF4 promotes angiogenesis and neuronal cell death and confers ferroptosis in a xCT-dependent manner. Oncogene. 2017;36(40):5593–5608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tarangelo A, et al. p53 suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Rep. 2018;22(3):569–575

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Li D, Li Y. The interaction between ferroptosis and lipid metabolism in cancer. Signal Transduct Target Ther. 2020;5(1):108

    Article  PubMed  PubMed Central  Google Scholar 

  56. Yang WS, Stockwell BR. Ferroptosis: death by lipid peroxidation. Trends Cell Biol. 2016;26(3):165–176

    Article  CAS  PubMed  Google Scholar 

  57. Gan B. ACSL4, PUFA, and ferroptosis: new arsenal in anti-tumor immunity. Signal Transduct Target Ther. 2022;7(1):128

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  59. Lagrost L, Masson D. The expanding role of lyso-phosphatidylcholine acyltransferase-3 (LPCAT3), a phospholipid remodeling enzyme, in health and disease. Curr Opin Lipidol. 2022;33(3):193–198

    Article  CAS  PubMed  Google Scholar 

  60. Magtanong L, et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol. 2019;26(3):420–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Reed A, et al. LPCAT3 inhibitors remodel the polyunsaturated phospholipid content of human cells and protect from ferroptosis. ACS Chem Biol. 2022;17(6):1607–1618

    Article  CAS  PubMed  Google Scholar 

  62. Wang Y, et al. ACSL4 deficiency confers protection against ferroptosis-mediated acute kidney injury. Redox Biol. 2022;51: 102262

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Averill-Bates DA. The antioxidant glutathione. Vitam Horm. 2023;121:109–141

    Article  CAS  PubMed  Google Scholar 

  65. Brigelius-Flohe R, Flohe L. Regulatory phenomena in the glutathione peroxidase superfamily. Antioxid Redox Signal. 2020;33(7):498–516

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Yang WS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1–2):317–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Eaton JK, et al. Selective covalent targeting of GPX4 using masked nitrile-oxide electrophiles. Nat Chem Biol. 2020;16(5):497–506

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Warner GJ, et al. Inhibition of selenoprotein synthesis by selenocysteine tRNA[Ser]Sec lacking isopentenyladenosine. J Biol Chem. 2000;275(36):28110–28119

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Kraft VAN, et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent Sci. 2020;6(1):41–53

    Article  CAS  PubMed  Google Scholar 

  73. Liang JY, et al. A novel ferroptosis-related gene signature for overall survival prediction in patients with hepatocellular carcinoma. Int J Biol Sci. 2020;16(13):2430–2441

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Shen Y, et al. Iron metabolism gene expression and prognostic features of hepatocellular carcinoma. J Cell Biochem. 2018;119(11):9178–9204

    Article  CAS  PubMed  Google Scholar 

  75. Liu Z, et al. The identification and validation of two heterogenous subtypes and a risk signature based on ferroptosis in hepatocellular carcinoma. Front Oncol. 2021;11: 619242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tang B, et al. The ferroptosis and iron-metabolism signature robustly predicts clinical diagnosis, prognosis and immune microenvironment for hepatocellular carcinoma. Cell Commun Signal. 2020;18(1):174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Zhang T, et al. ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of iron regulatory protein 1. Nat Cancer. 2022;3(1):75–89

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  78. Zhang L, et al. Sorafenib triggers ferroptosis via inhibition of HBXIP/SCD axis in hepatocellular carcinoma. Acta Pharmacol Sin. 2022;44:622–634

    Article  PubMed  Google Scholar 

  79. Ren X, et al. Integrative bioinformatics and experimental analysis revealed TEAD as novel prognostic target for hepatocellular carcinoma and its roles in ferroptosis regulation. Aging (Albany NY). 2022;14(2):961–974

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  80. Wang Q, et al. RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA. Exp Cell Res. 2021;399(1): 112453

    Article  CAS  PubMed  Google Scholar 

  81. Faubert B, et al. Lactate metabolism in human lung tumors. Cell. 2017;171(2):358–371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Zhao Y, et al. HCAR1/MCT1 regulates tumor ferroptosis through the lactate-mediated AMPK-SCD1 activity and its therapeutic implications. Cell Rep. 2020;33(10): 108487

    Article  CAS  PubMed  Google Scholar 

  83. Yao F, et al. A targetable LIFR-NF-kappaB-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis. Nat Commun. 2021;12(1):7333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Liu Y, et al. PCDHB14 promotes ferroptosis and is a novel tumor suppressor in hepatocellular carcinoma. Oncogene. 2022;41(27):3570–3583

    Article  CAS  PubMed  Google Scholar 

  85. Zhang Y, et al. Long noncoding RNA NEAT1 promotes ferroptosis by modulating the miR-362-3p/MIOX axis as a ceRNA. Cell Death Differ. 2022;29(9):1850–1863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Yuan Y, et al. CLTRN, regulated by NRF1/RAN/DLD protein complex, enhances radiation sensitivity of hepatocellular carcinoma cells through ferroptosis pathway. Int J Radiat Oncol Biol Phys. 2021;110(3):859–871

    Article  PubMed  Google Scholar 

  87. Suzuki S, et al. GLS2 is a tumor suppressor and a regulator of ferroptosis in hepatocellular carcinoma. Cancer Res. 2022;82(18):3209–3222

    Article  CAS  PubMed  Google Scholar 

  88. Colagrande S, et al. Challenges of advanced hepatocellular carcinoma. World J Gastroenterol. 2016;22(34):7645–7659

    Article  PubMed  PubMed Central  Google Scholar 

  89. Cabral LKD, Tiribelli C, Sukowati CHC. Sorafenib resistance in hepatocellular carcinoma: the relevance of genetic heterogeneity. Cancers (Basel). 2020;12:6

    Article  Google Scholar 

  90. Gao R, et al. YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. EMBO Mol Med. 2021;13(12): e14351

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Qiu Y, et al. Identification of ABCC5 among ATP-binding cassette transporter family as a new biomarker for hepatocellular carcinoma based on bioinformatics analysis. Int J Gen Med. 2021;14:7235–7246

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Huang W, et al. ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma. Neoplasia. 2021;23(12):1227–1239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Wang Q, et al. GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis via inhibition of NRF2/GPX4 axis. Cell Death Dis. 2021;12(5):426

    Article  PubMed  PubMed Central  Google Scholar 

  94. Sun J, et al. Quiescin sulfhydryl oxidase 1 promotes sorafenib-induced ferroptosis in hepatocellular carcinoma by driving EGFR endosomal trafficking and inhibiting NRF2 activation. Redox Biol. 2021;41: 101942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wei L, et al. Genome-wide CRISPR/Cas9 library screening identified PHGDH as a critical driver for Sorafenib resistance in HCC. Nat Commun. 2019;10(1):4681

    Article  MathSciNet  PubMed  PubMed Central  Google Scholar 

  96. Byun JK, et al. Macropinocytosis is an alternative pathway of cysteine acquisition and mitigates sorafenib-induced ferroptosis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2022;41(1):98

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Bruix J, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66

    Article  CAS  PubMed  Google Scholar 

  98. Heo YA, Syed YY. Regorafenib: a review in hepatocellular carcinoma. Drugs. 2018;78(9):951–958

    Article  CAS  PubMed  Google Scholar 

  99. Qin S, et al. Donafenib versus sorafenib in first-line treatment of unresectable or metastatic hepatocellular carcinoma: a randomized, open-label, parallel-controlled phase II–III trial. J Clin Oncol. 2021;39(27):3002–3011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Kudo M, et al. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018;391(10126):1163–1173

    Article  CAS  PubMed  Google Scholar 

  101. Iseda N, et al. Ferroptosis is induced by lenvatinib through fibroblast growth factor receptor-4 inhibition in hepatocellular carcinoma. Cancer Sci. 2022;113(7):2272–2287

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wu WC, et al. Lenvatinib combined with nivolumab in advanced hepatocellular carcinoma-real-world experience. Invest New Drugs. 2022;40(4):789–797

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chiew Woon L, Joycelyn Jie Xin L, Su Pin C. Nivolumab for the treatment of hepatocellular carcinoma. Expert Opin Biol Ther. 2020;20(7):687–693

    Article  CAS  PubMed  Google Scholar 

  104. Wu F, et al. Phase 2 evaluation of neoadjuvant intensity-modulated radiotherapy in centrally located hepatocellular carcinoma: a nonrandomized controlled trial. JAMA Surg. 2022;157(12):1089–1096

    Article  PubMed  PubMed Central  Google Scholar 

  105. Liao J, et al. Methyltransferase 1 is required for nonhomologous end-joining repair and renders hepatocellular carcinoma resistant to radiotherapy. Hepatology. 2022;77:1896–1910

    Article  PubMed  Google Scholar 

  106. Ye LF, et al. Radiation-induced lipid peroxidation triggers ferroptosis and synergizes with ferroptosis inducers. ACS Chem Biol. 2020;15(2):469–484

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Yang M, et al. COMMD10 inhibits HIF1alpha/CP loop to enhance ferroptosis and radiosensitivity by disrupting Cu-Fe balance in hepatocellular carcinoma. J Hepatol. 2022;76(5):1138–1150

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  108. Chen Q, et al. SOCS2-enhanced ubiquitination of SLC7A11 promotes ferroptosis and radiosensitization in hepatocellular carcinoma. Cell Death Differ. 2023;30(1):137–151

    Article  CAS  PubMed  Google Scholar 

  109. Lei G, et al. The role of ferroptosis in ionizing radiation-induced cell death and tumor suppression. Cell Res. 2020;30(2):146–162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Du J, et al. DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic Biol Med. 2019;131:356–369

    Article  CAS  PubMed  Google Scholar 

  111. Su Y, et al. Dihydroartemisinin induces ferroptosis in HCC by promoting the formation of PEBP1/15-LO. Oxid Med Cell Longev. 2021;2021:3456725

    Article  PubMed  PubMed Central  Google Scholar 

  112. Li X, et al. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat Rev Cancer. 2021;21(9):541–557

    Article  CAS  PubMed  Google Scholar 

  113. Wang J, et al. Identification and validation of ferroptosis-associated gene-based on immune score as prognosis markers for hepatocellular carcinoma patients. J Gastrointest Oncol. 2021;12(5):2345–2360

    Article  PubMed  PubMed Central  Google Scholar 

  114. Xu J, et al. The NCX1/TRPC6 complex mediates TGFbeta-driven migration and invasion of human hepatocellular carcinoma cells. Cancer Res. 2018;78(10):2564–2576

    Article  CAS  PubMed  Google Scholar 

  115. Kim DH, et al. TGF-beta1-mediated repression of SLC7A11 drives vulnerability to GPX4 inhibition in hepatocellular carcinoma cells. Cell Death Dis. 2020;11(5):406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wang S, Chen L, Liu W. Matrix stiffness-dependent STEAP3 coordinated with PD-L2 identify tumor responding to sorafenib treatment in hepatocellular carcinoma. Cancer Cell Int. 2022;22(1):318

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. He Q, et al. IL-1beta-induced elevation of solute carrier family 7 member 11 promotes hepatocellular carcinoma metastasis through up-regulating programmed death ligand 1 and colony-stimulating factor 1. Hepatology. 2021;74(6):3174–3193

    Article  CAS  PubMed  Google Scholar 

  118. Liu DL, et al. Ferroptosis regulator modification patterns and tumor microenvironment immune infiltration characterization in hepatocellular carcinoma. Front Mol Biosci. 2022;9: 807502

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zheng J, Conrad M. The metabolic underpinnings of ferroptosis. Cell Metab. 2020;32(6):920–937

    Article  CAS  PubMed  Google Scholar 

  120. Acharya N, et al. Endogenous glucocorticoid signaling regulates CD8(+) T cell differentiation and development of dysfunction in the tumor microenvironment. Immunity. 2020;53(3):658–671

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Ai L, Xu A, Xu J. Roles of PD-1/PD-L1 pathway: signaling, cancer, and beyond. Adv Exp Med Biol. 2020;1248:33–59

    Article  CAS  PubMed  Google Scholar 

  122. Hu B, et al. IFNalpha potentiates anti-PD-1 efficacy by remodeling glucose metabolism in the hepatocellular carcinoma microenvironment. Cancer Discov. 2022;12(7):1718–1741

    Article  CAS  PubMed  Google Scholar 

  123. Kong R, et al. IFNgamma-mediated repression of system xc(-) drives vulnerability to induced ferroptosis in hepatocellular carcinoma cells. J Leukoc Biol. 2021;110(2):301–314

    Article  CAS  PubMed  Google Scholar 

  124. Wang W, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569(7755):270–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Liao P, et al. CD8(+) T cells and fatty acids orchestrate tumor ferroptosis and immunity via ACSL4. Cancer Cell. 2022;40(4):365–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Xu S, et al. Uptake of oxidized lipids by the scavenger receptor CD36 promotes lipid peroxidation and dysfunction in CD8(+) T cells in tumors. Immunity. 2021;54(7):1561–1577

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Ma X, et al. CD36-mediated ferroptosis dampens intratumoral CD8(+) T cell effector function and impairs their antitumor ability. Cell Metab. 2021;33(5):1001–1012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kalathil S, et al. Higher frequencies of GARP(+)CTLA-4(+)Foxp3(+) T regulatory cells and myeloid-derived suppressor cells in hepatocellular carcinoma patients are associated with impaired T-cell functionality. Cancer Res. 2013;73(8):2435–2444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Zhang C, et al. Hepatitis B-induced IL8 promotes hepatocellular carcinoma venous metastasis and intrahepatic Treg accumulation. Cancer Res. 2021;81(9):2386–2398

    Article  CAS  PubMed  Google Scholar 

  130. Liu J, et al. Lipid-related FABP5 activation of tumor-associated monocytes fosters immune privilege via PD-L1 expression on Treg cells in hepatocellular carcinoma. Cancer Gene Ther. 2022;29(12):1951–1960

    Article  PubMed  Google Scholar 

  131. Wu SP, et al. Stromal PD-L1-positive regulatory T cells and PD-1-positive CD8-positive T cells define the response of different subsets of non-small cell lung cancer to PD-1/PD-L1 blockade immunotherapy. J Thorac Oncol. 2018;13(4):521–532

    Article  PubMed  Google Scholar 

  132. Zhang W, et al. Thiostrepton induces ferroptosis in pancreatic cancer cells through STAT3/GPX4 signalling. Cell Death Dis. 2022;13(7):630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Ouyang S, et al. Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer. Redox Biol. 2022;52: 102317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Xu C, et al. The glutathione peroxidase Gpx4 prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity. Cell Rep. 2021;35(11): 109235

    Article  CAS  PubMed  Google Scholar 

  135. Suthen S, et al. Hypoxia-driven immunosuppression by Treg and type-2 conventional dendritic cells in HCC. Hepatology. 2022;76(5):1329–1344

    Article  CAS  PubMed  Google Scholar 

  136. Jiang Y, et al. EGLN1/c-myc induced lymphoid-specific helicase inhibits ferroptosis through lipid metabolic gene expression changes. Theranostics. 2017;7(13):3293–3305

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Wu T, Dai Y. Tumor microenvironment and therapeutic response. Cancer Lett. 2017;387:61–68

    Article  CAS  PubMed  Google Scholar 

  138. Jiang Y, et al. Promotion of epithelial-mesenchymal transformation by hepatocellular carcinoma-educated macrophages through Wnt2b/beta-catenin/c-Myc signaling and reprogramming glycolysis. J Exp Clin Cancer Res. 2021;40(1):13

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  139. Handa P, et al. Iron alters macrophage polarization status and leads to steatohepatitis and fibrogenesis. J Leukoc Biol. 2019;105(5):1015–1026

    Article  CAS  PubMed  Google Scholar 

  140. Zhou Y, et al. Iron overloaded polarizes macrophage to proinflammation phenotype through ROS/acetyl-p53 pathway. Cancer Med. 2018;7(8):4012–4022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Hao X, et al. Inhibition of APOC1 promotes the transformation of M2 into M1 macrophages via the ferroptosis pathway and enhances anti-PD1 immunotherapy in hepatocellular carcinoma based on single-cell RNA sequencing. Redox Biol. 2022;56: 102463

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Zhang Q, et al. Landscape and dynamics of single immune cells in hepatocellular carcinoma. Cell. 2019;179(4):829–845

    Article  CAS  PubMed  Google Scholar 

  143. Ringelhan M, et al. The immunology of hepatocellular carcinoma. Nat Immunol. 2018;19(3):222–232

    Article  CAS  PubMed  Google Scholar 

  144. Hoechst B, et al. Myeloid derived suppressor cells inhibit natural killer cells in patients with hepatocellular carcinoma via the NKp30 receptor. Hepatology. 2009;50(3):799–807

    Article  CAS  PubMed  Google Scholar 

  145. Hoechst B, et al. A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4(+)CD25(+)Foxp3(+) T cells. Gastroenterology. 2008;135(1):234–243

    Article  CAS  PubMed  Google Scholar 

  146. Li S, et al. TLR2 agonist promotes myeloid-derived suppressor cell polarization via Runx1 in hepatocellular carcinoma. Int Immunopharmacol. 2022;111:2

    Article  Google Scholar 

  147. Kim R, et al. Ferroptosis of tumour neutrophils causes immune suppression in cancer. Nature. 2022;612(7939):338–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Zhu H, et al. Asah2 represses the p53-Hmox1 axis to protect myeloid-derived suppressor cells from ferroptosis. J Immunol. 2021;206(6):1395–1404

    Article  CAS  PubMed  Google Scholar 

  149. Liu P, Chen L, Zhang H. Natural killer cells in liver disease and hepatocellular carcinoma and the NK cell-based immunotherapy. J Immunol Res. 2018;2018:1206737

    Article  PubMed  PubMed Central  Google Scholar 

  150. Paust S, et al. Critical role for the chemokine receptor CXCR6 in NK cell-mediated antigen-specific memory of haptens and viruses. Nat Immunol. 2010;11(12):1127–1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Lassen MG, et al. Intrahepatic IL-10 maintains NKG2A+Ly49- liver NK cells in a functionally hyporesponsive state. J Immunol. 2010;184(5):2693–2701

    Article  CAS  PubMed  Google Scholar 

  152. Wu Y, et al. Monocyte/macrophage-elicited natural killer cell dysfunction in hepatocellular carcinoma is mediated by CD48/2B4 interactions. Hepatology. 2013;57(3):1107–1116

    Article  MathSciNet  CAS  PubMed  Google Scholar 

  153. Chen Q, Liu L, Ni S. Screening of ferroptosis-related genes in sepsis-induced liver failure and analysis of immune correlation. PeerJ. 2022;10: e13757

    Article  PubMed  PubMed Central  Google Scholar 

  154. Wculek SK, et al. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2020;20(1):7–24

    Article  CAS  PubMed  Google Scholar 

  155. Wang S, et al. Blocking CD47 promotes antitumour immunity through CD103(+) dendritic cell-NK cell axis in murine hepatocellular carcinoma model. J Hepatol. 2022;77(2):467–478

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Wareing TC, Gentile P, Phan AN. Biomass-based carbon dots: current development and future perspectives. ACS Nano. 2021;15(10):15471–15501

    Article  CAS  PubMed  Google Scholar 

  158. Yao L, et al. Carbon quantum dots-based nanozyme from coffee induces cancer cell ferroptosis to activate antitumor immunity. ACS Nano. 2022;16(6):9228–9239

    Article  CAS  PubMed  Google Scholar 

  159. Zhang M, et al. A self-amplifying nanodrug to manipulate the Janus-faced nature of ferroptosis for tumor therapy. Nanoscale Horiz. 2022;7(2):198–210

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by the China Postdoctoral Science Foundation (2020M682779 and 2021T140295), National Natural Science Foundation of China (82303446), Shenzhen High-level Hospital Construction Fund, and Peking University Shenzhen Hospital Scientific Research Fund (KYQD2023303).

Author information

Authors and Affiliations

  1. School of Public Health, Guangdong Medical University, Zhanjiang, Guangdong, China

    Yuqian Mo

  2. Department of Ophthalmology, Affiliated Eye Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China

    Zhilin Zou

  3. Department of Hepatobiliary and Pancreatic Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China

    Erbao Chen

Authors
  1. Yuqian Mo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zhilin Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Erbao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

EC designed the review. YM, ZZ, and EC drafted the manuscript. YM made the figures. YM, ZZ, and EC revised the manuscript. The authors approved the final manuscript.

Corresponding author

Correspondence to Erbao Chen.

Ethics declarations

Conflict of interest

Yuqian Mo, Zhilin Zou and Erbao Chen declare no conflict of interest.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Yuqian Mo and Zhilin Zou contributed equally to this work and share first authorship.

The original version of this article was revised: Article note on author contribution updated.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mo, Y., Zou, Z. & Chen, E. Targeting ferroptosis in hepatocellular carcinoma. Hepatol Int 18, 32–49 (2024). https://doi.org/10.1007/s12072-023-10593-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-023-10593-y

Keywords

Search

Navigation