Ferroptosis in hepatocellular carcinoma: mechanisms and targeted therapy

ABSTRACT Hepatocellular carcinoma is the most prevalent form of primary liver cancer with a multifactorial aetiology comprising genetic, environmental, and behavioural factors. Evading cell

death is a defining hallmark of hepatocellular carcinoma, underpinning tumour growth, progression, and therapy resistance. Ferroptosis is a form of nonapoptotic cell death driven by an array

of cellular events, including intracellular iron overload, free radical production, lipid peroxidation and activation of various cell death effectors, ultimately leading to rupture of the

plasma membrane. Although induction of ferroptosis is an emerging strategy to suppress hepatocellular carcinoma, malignant cells manage to develop adaptive mechanisms, conferring resistance

to ferroptosis and ferroptosis-inducing drugs. Herein, we aim at elucidating molecular mechanisms and signalling pathways involved in ferroptosis and offer our opinions on druggable targets

and new therapeutic strategy in an attempt to restrain the growth and progression of hepatocellular carcinoma through induction of ferroptotic cell death. Access through your institution Buy

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OTHERS FERROPTOSIS: A NEW HUNTER OF HEPATOCELLULAR CARCINOMA Article Open access 13 March 2024 THE EMERGING ROLE OF FERROPTOSIS IN NON-CANCER LIVER DISEASES: HYPE OR INCREASING HOPE? Article

Open access 09 July 2020 TARGETING FERROPTOSIS AS A VULNERABILITY IN CANCER Article 25 March 2022 DATA AVAILABILITY Not applicable. REFERENCES * Röcken C, Carl-McGrath S. Pathology and

pathogenesis of hepatocellular carcinoma. Digestive Dis. 2001;19:269–78. Article  Google Scholar  * Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer

statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: Cancer J Clin. 2021;71:209–49. Google Scholar  * Ahmed O, Liu L, Gayed A, Baadh

A, Patel M, Tasse J, et al. The changing face of hepatocellular carcinoma: forecasting prevalence of nonalcoholic steatohepatitis and hepatitis C cirrhosis. J Clin Exp Hepatol. 2019;9:50–55.

Article  Google Scholar  * Kanwal F, Hoang T, Kramer JR, Asch SM, Goetz MB, Zeringue A, et al. Increasing prevalence of HCC and cirrhosis in patients with chronic hepatitis C virus

infection. Gastroenterology. 2011;140:1182–8. e1181. Article  Google Scholar  * Siegel AB, Zhu AX. Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential

link. Cancer: Interdiscip Int J Am Cancer Soc. 2009;115:5651–61. Article  Google Scholar  * Gan L, Liu Z, Sun C. Obesity linking to hepatocellular carcinoma: a global view. Biochimica et

Biophysica Acta (BBA)-Rev Cancer. 2018;1869:97–102. Article  CAS  Google Scholar  * Cholankeril G, Patel R, Khurana S, Satapathy SK. Hepatocellular carcinoma in non-alcoholic

steatohepatitis: current knowledge and implications for management. World J Hepatol. 2017;9:533. Article  Google Scholar  * Zaki MYW, Mahdi AK, Patman GL, Whitehead A, Maurício JP, McCain

MV, et al. Key features of the environment promoting liver cancer in the absence of cirrhosis. Sci Rep. 2021;11:1–17. Article  Google Scholar  * Sun Y, Peng Z. Programmed cell death and

cancer. Postgrad Med J. 2009;85:134–40. Article  CAS  Google Scholar  * Aizawa S, Brar G, Tsukamoto H. Cell death and liver disease. Gut liver. 2020;14:20. Article  CAS  Google Scholar  *

Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death

Differ. 2018;25:486–541. Article  Google Scholar  * Tang D, Kang R, Berghe TV, Vandenabeele P, Kroemer G. The molecular machinery of regulated cell death. Cell Res. 2019;29:347–64. Article 

CAS  Google Scholar  * Dionísio P, Amaral J, Rodrigues C. Oxidative stress and regulated cell death in Parkinson’s disease. Ageing Res Rev. 2021;67:101263. * Stockwell BR, Friedmann Angeli

JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171:273–85. Article  CAS  Google Scholar

  * Chen X, Li J, Kang R, Klionsky DJ, Tang D. Ferroptosis: machinery and regulation. Autophagy. 2020; https://doi.org/10.1080/15548627.2020.1810918. * Chang W-T, Bow Y-D, Fu P-J, Li C-Y, Wu

C-Y, Chang Y-H, et al. A marine terpenoid, heteronemin, induces both the apoptosis and ferroptosis of hepatocellular carcinoma cells and involves the ROS and MAPK pathways. Oxid Med Cell

Longev. 2021;2021:7689045. Google Scholar  * Nie J, Lin B, Zhou M, Wu L, Zheng T. Role of ferroptosis in hepatocellular carcinoma. J Cancer Res Clin Oncol. 2018;144:2329–37. Article  CAS 

Google Scholar  * Lakhal-Littleton S. Mechanisms of cardiac iron homeostasis and their importance to heart function. Free Radic Biol Med. 2019;133:234–7. Article  CAS  Google Scholar  * Bi

Y, Ajoolabady A, Demillard LJ, Yu W, Hilaire ML, Zhang Y, et al. Dysregulation of iron metabolism in cardiovascular diseases: from iron deficiency to iron overload. Biochem Pharmacol.

2021;190:114661. * Aisen P, Wessling-Resnick M, Leibold EA. Iron metabolism. Curr Opin Chem Biol. 1999;3:200–6. Article  CAS  Google Scholar  * Wang C-Y, Babitt JL. Liver iron sensing and

body iron homeostasis. Blood, J Am Soc Hematol. 2019;133:18–29. CAS  Google Scholar  * Wang J, Pantopoulos K. Regulation of cellular iron metabolism. Biochemical J. 2011;434:365–81. Article

  CAS  Google Scholar  * Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin. Semin Hematol. 1998;35:35–54. * Newman R, Schneider C, Sutherland R,

Vodinelich L, Greaves M. The transferrin receptor. Trends Biochemical Sci. 1982;7:397–400. Article  CAS  Google Scholar  * Montalbetti N, Simonin A, Kovacs G, Hediger MA. Mammalian iron

transporters: families SLC11 and SLC40. Mol Asp Med. 2013;34:270–87. Article  CAS  Google Scholar  * Munro HN, Linder MC. Ferritin: structure, biosynthesis, and role in iron metabolism.

Physiological Rev. 1978;58:317–96. Article  CAS  Google Scholar  * Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ 3rd, et al. Autophagy promotes ferroptosis by degradation of ferritin.

Autophagy. 2016;12:1425–8. Article  CAS  Google Scholar  * Mayr R, Griffiths WJ, Hermann M, McFarlane I, Halsall DJ, Finkenstedt A, et al. Identification of mutations in SLC40A1 that affect

ferroportin function and phenotype of human ferroportin iron overload. Gastroenterology. 2011;140:2056–63. e2051. Article  CAS  Google Scholar  * Li J, Liu J, Xu Y, Wu R, Chen X, Song X, et

al. Tumor heterogeneity in autophagy-dependent ferroptosis. Autophagy. 2021; https://doi.org/10.1080/15548627.2021.1872241. * Breuer W, Hershko C, Cabantchik Z. The importance of

non-transferrin bound iron in disorders of iron metabolism. Transfus Sci. 2000;23:185–92. Article  CAS  Google Scholar  * Lane D, Merlot A, Huang M-H, Bae D-H, Jansson P, Sahni S, et al.

Cellular iron uptake, trafficking and metabolism: key molecules and mechanisms and their roles in disease. Biochimica et Biophysica Acta (BBA)-Mol Cell Res. 2015;1853:1130–44. Article  CAS 

Google Scholar  * Knutson MD. Non-transferrin-bound iron transporters. Free Radic Biol Med. 2019;133:101–11. Article  CAS  Google Scholar  * Song X, Zhu S, Chen P, Hou W, Wen Q, Liu J, et

al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc–activity. Curr Biol. 2018;28:2388–99. e2385. Article  CAS  Google Scholar  * Yu Y, Jiang L, Wang

H, Shen Z, Cheng Q, Zhang P, et al. Hepatic transferrin plays a role in systemic iron homeostasis and liver ferroptosis. Blood. 2020;136:726–39. Article  CAS  Google Scholar  * Chen X, Yu C,

Kang R, Tang D. Iron metabolism in ferroptosis. Front Cell Dev Biol. 2020;8:590226. * Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an

iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72. Article  CAS  Google Scholar  * Paterek A, Mackiewicz U, Mączewski M. Iron and the heart: a paradigm shift from

systemic to cardiomyocyte abnormalities. J Cell Physiol. 2019;234:21613–29. Article  CAS  Google Scholar  * Vela D. Keeping heart homeostasis in check through the balance of iron metabolism.

Acta Physiologica. 2020;228:e13324. Article  CAS  Google Scholar  * Bogdan AR, Miyazawa M, Hashimoto K, Tsuji Y. Regulators of iron homeostasis: new players in metabolism, cell death, and

disease. Trends biochemical Sci. 2016;41:274–86. Article  CAS  Google Scholar  * Du J, Wang T, Li Y, Zhou Y, Wang X, Yu X, et al. DHA inhibits proliferation and induces ferroptosis of

leukemia cells through autophagy dependent degradation of ferritin. Free Radic Biol Med. 2019;131:356–69. Article  CAS  Google Scholar  * Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X.

Ferroptosis is an autophagic cell death process. Cell Res. 2016;26:1021–32. Article  CAS  Google Scholar  * Chen X, Yu C, Kang R, Tang D. Iron metabolism in ferroptosis. Front Cell Dev Biol.

2020;8:590226. Article  Google Scholar  * Higdon A, Diers AR, Oh JY, Landar A, Darley-Usmar VM. Cell signalling by reactive lipid species: new concepts and molecular mechanisms. Biochemical

J. 2012;442:453–64. Article  CAS  Google Scholar  * Latunde-Dada GO. Ferroptosis: role of lipid peroxidation, iron and ferritinophagy. Biochimica et Biophysica Acta (BBA)-Gen Subj.

2017;1861:1893–1900. Article  CAS  Google Scholar  * Guo J, Xu B, Han Q, Zhou H, Xia Y, Gong C, et al. Ferroptosis: a novel anti-tumor action for cisplatin. Cancer Res Treat. 2018;50:445.

Article  CAS  Google Scholar  * Sheng X, Shan C, Liu J, Yang J, Sun B, Chen D. Theoretical insights into the mechanism of ferroptosis suppression via inactivation of a lipid peroxide radical

by liproxstatin-1. Phys Chem Chem Phys. 2017;19:13153–9. Article  CAS  Google Scholar  * Zilka O, Shah R, Li B, Friedmann Angeli JP, Griesser M, Conrad M, et al. On the mechanism of

cytoprotection by ferrostatin-1 and liproxstatin-1 and the role of lipid peroxidation in ferroptotic cell death. ACS Cent Sci. 2017;3:232–43. Article  CAS  Google Scholar  * Doll S, Proneth

B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13:91–98. Article  CAS  Google

Scholar  * Yang WS, Kim KJ, Gaschler MM, Patel M, Shchepinov MS, Stockwell BR. Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci USA.

2016;113:E4966–75. Article  CAS  Google Scholar  * Yuan H, Li X, Zhang X, Kang R, Tang D. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochemical biophysical Res

Commun. 2016;478:1338–43. Article  CAS  Google Scholar  * Dixon SJ, Winter GE, Musavi LS, Lee ED, Snijder B, Rebsamen M, et al. Human haploid cell genetics reveals roles for lipid metabolism

genes in nonapoptotic cell death. ACS Chem Biol. 2015;10:1604–9. Article  CAS  Google Scholar  * Soupene E, Kuypers FA. Mammalian long-chain acyl-CoA synthetases. Exp Biol Med.

2008;233:507–21. Article  CAS  Google Scholar  * Shindou H, Shimizu T. Acyl-CoA: lysophospholipid acyltransferases. J Biol Chem. 2009;284:1–5. Article  CAS  Google Scholar  * Yang W-H, Huang

Z, Wu J, Ding C-KC, Murphy SK, Chi J-T. A TAZ–ANGPTL4–NOX2 axis regulates ferroptotic cell death and chemoresistance in epithelial ovarian cancerTAZ promotes ferroptosis in OvCa. Mol Cancer

Res. 2020;18:79–90. Article  CAS  Google Scholar  * Kagan VE, Mao G, Qu F, Angeli JPF, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem

Biol. 2017;13:81–90. Article  CAS  Google Scholar  * Kreft H, Jetz W. Global patterns and determinants of vascular plant diversity. Proc Natl Acad Sci USA. 2007;104:5925–30. Article  CAS 

Google Scholar  * Zou Y, Li H, Graham ET, Deik AA, Eaton JK, Wang W, et al. Cytochrome P450 oxidoreductase contributes to phospholipid peroxidation in ferroptosis. Nat Chem Biol.

2020;16:302–9. Article  CAS  Google Scholar  * Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, et al. Role of mitochondria in ferroptosis. Mol Cell. 2019;73:354–63. e353. Article  CAS

  Google Scholar  * Hinman A, Holst CR, Latham JC, Bruegger JJ, Ulas G, McCusker KP, et al. Vitamin E hydroquinone is an endogenous regulator of ferroptosis via redox control of

15-lipoxygenase. PLoS ONE. 2018;13:e0201369. Article  Google Scholar  * Kuang F, Liu J, Tang D, Kang R. Oxidative damage and antioxidant defense in ferroptosis. Front Cell Dev Biol.

2020;8:969. Article  Google Scholar  * Bai Y, Meng L, Han L, Jia Y, Zhao Y, Gao H, et al. Lipid storage and lipophagy regulates ferroptosis. Biochem Biophys Res Commun. 2019;508:997–1003.

Article  CAS  Google Scholar  * Xu X, Zhang X, Wei C, Zheng D, Lu X, Yang Y, et al. Targeting SLC7A11 specifically suppresses the progression of colorectal cancer stem cells via inducing

ferroptosis. Eur J Pharm Sci. 2020;152:105450. Article  CAS  Google Scholar  * Chen X, Kang R, Kroemer G, Tang D. Broadening horizons: the role of ferroptosis in cancer. Nat Rev Clin Oncol.

2021;18:280–96. Article  CAS  Google Scholar  * Zheng J, Sato M, Mishima E, Sato H, Proneth B, Conrad M. Sorafenib fails to trigger ferroptosis across a wide range of cancer cell lines. Cell

death Dis. 2021;12:1–10. Article  Google Scholar  * Sato H, Tamba M, Ishii T, Bannai S. Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two

distinct proteins. J Biol Chem. 1999;274:11455–8. Article  CAS  Google Scholar  * Harris IS, Treloar AE, Inoue S, Sasaki M, Gorrini C, Lee KC, et al. Glutathione and thioredoxin antioxidant

pathways synergize to drive cancer initiation and progression. Cancer Cell. 2015;27:211–22. Article  CAS  Google Scholar  * Banjac A, Perisic T, Sato H, Seiler A, Bannai S, Weiss N, et al.

The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death. Oncogene. 2008;27:1618–28. Article  CAS  Google Scholar  * Jiang L, Kon N, Li T, Wang

S-J, Su T, Hibshoosh H, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62. Article  CAS  Google Scholar  * Cao JY, Dixon SJ. Mechanisms of

ferroptosis. Cell Mol Life Sci. 2016;73:2195–209. Article  CAS  Google Scholar  * Seiler A, Schneider M, Förster H, Roth S, Wirth EK, Culmsee C, et al. Glutathione peroxidase 4 senses and

translates oxidative stress into 12/15-lipoxygenase dependent-and AIF-mediated cell death. Cell Metab. 2008;8:237–48. Article  CAS  Google Scholar  * Yang WS, SriRamaratnam R, Welsch ME,

Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–31. Article  CAS  Google Scholar  * Friedmann Angeli JP, Schneider M,

Proneth B, Tyurina YY, Tyurin VA, Hammond VJ, et al. Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol. 2014;16:1180–91. Article  CAS  Google

Scholar  * Guerriero E, Capone F, Accardo M, Sorice A, Costantini M, Colonna G, et al. GPX4 and GPX7 over-expression in human hepatocellular carcinoma tissues. Eur J Histochemistry.

2015;59:2540. Article  CAS  Google Scholar  * Gan B. Mitochondrial regulation of ferroptosis. J Cell Biol. 2021;220:e202105043. Article  CAS  Google Scholar  * Bersuker K, Hendricks JM, Li

Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature. 2019;575:688–92. Article  CAS  Google Scholar  * Dai E, Zhang W,

Cong D, Kang R, Wang J, Tang D. AIFM2 blocks ferroptosis independent of ubiquinol metabolism. Biochemical Biophysical Res Commun. 2020;523:966–71. Article  CAS  Google Scholar  * Martinez

VD, Vucic EA, Pikor LA, Thu KL, Hubaux R, Lam WL. Frequent concerted genetic mechanisms disrupt multiple components of the NRF2 inhibitor KEAP1/CUL3/RBX1 E3-ubiquitin ligase complex in

thyroid cancer. Mol Cancer. 2013;12:1–6. Article  Google Scholar  * Rada P, Rojo AI, Evrard-Todeschi N, Innamorato NG, Cotte A, Jaworski T, et al. Structural and functional characterization

of Nrf2 degradation by the glycogen synthase kinase 3/β-TrCP axis. Mol Cell Biol. 2012;32:3486–99. Article  CAS  Google Scholar  * Zhang J, Zhang J, Ni H, Wang Y, Katwal G, Zhao Y, et al.

Downregulation of XBP1 protects kidney against ischemia-reperfusion injury via suppressing HRD1-mediated NRF2 ubiquitylation. Cell Death Discov. 2021;7:1–13. Google Scholar  * Nguyen T, Nioi

P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284:13291–5. Article  CAS  Google Scholar  * Dodson M,

Castro-Portuguez R, Zhang DD. NRF2 plays a critical role in mitigating lipid peroxidation and ferroptosis. Redox Biol. 2019;23:101107. Article  CAS  Google Scholar  * Kerins MJ, Ooi A. The

roles of NRF2 in modulating cellular iron homeostasis. Antioxid Redox Signal. 2018;29:1756–73. Article  CAS  Google Scholar  * Agyeman AS, Chaerkady R, Shaw PG, Davidson NE, Visvanathan K,

Pandey A, et al. Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane-treated human breast epithelial cells reveals common expression profiles. Breast cancer Res Treat.

2012;132:175–87. Article  CAS  Google Scholar  * Harada N, Kanayama M, Maruyama A, Yoshida A, Tazumi K, Hosoya T, et al. Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts

lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages. Arch Biochem biophysics. 2011;508:101–9. Article  CAS  Google Scholar  * Chorley BN, Campbell MR, Wang X, Karaca M,

Sambandan D, Bangura F, et al. Identification of novel NRF2-regulated genes by ChIP-Seq: influence on retinoid X receptor alpha. Nucleic Acids Res. 2012;40:7416–29. Article  CAS  Google

Scholar  * Hübner R-H, Schwartz JD, De BP, Ferris B, Omberg L, Mezey JG, et al. Coordinate control of expression of Nrf2-modulated genes in the human small airway epithelium is highly

responsive to cigarette smoking. Mol Med. 2009;15:203–19. Article  Google Scholar  * Campbell MR, Karaca M, Adamski KN, Chorley BN, Wang X, Bell DA. Novel hematopoietic target genes in the

NRF2-mediated transcriptional pathway. Oxid Med Cell Longev. 2013;2013:120305. Article  Google Scholar  * Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R, et al. Activation of the p62‐Keap1-NRF2

pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2016;63:173–84. Article  CAS  Google Scholar  * Sun X, Niu X, Chen R, He W, Chen D, Kang R, et al.

Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology. 2016;64:488–500. Article  CAS  Google Scholar  * Wang H, Lin D, Yu Q, Li Z, Lenahan C, Dong

Y, et al. A promising future of ferroptosis in tumor therapy. Front Cell Dev Biol. 2021;9:1255. * Guo W, Zhou BP. Oncometabolite modification of Keap1 links GSTZ1 deficiency with cancer.

Genes Dis. 2019;6:333–4. Article  CAS  Google Scholar  * Wang Q, Bin C, Xue Q, Gao Q, Huang A, Wang K, et al. GSTZ1 sensitizes hepatocellular carcinoma cells to sorafenib-induced ferroptosis

via inhibition of NRF2/GPX4 axis. Cell Death Dis. 2021;12:1–16. Google Scholar  * Jedlitschky G, Burchell B, Keppler D. The multidrug resistance protein 5 functions as an ATP-dependent

export pump for cyclic nucleotides. J Biol Chem. 2000;275:30069–74. Article  CAS  Google Scholar  * Weaver DA, Crawford EL, Warner KA, Elkhairi F, Khuder SA, Willey JC. ABCC5, ERCC2, XPA and

XRCC1 transcript abundance levels correlate with cisplatin chemoresistance in non-small cell lung cancer cell lines. Mol Cancer. 2005;4:1–8. Article  Google Scholar  * Huang W, Chen K, Lu

Y, Zhang D, Cheng Y, Li L, et al. ABCC5 facilitates the acquired resistance of sorafenib through the inhibition of SLC7A11-induced ferroptosis in hepatocellular carcinoma. Neoplasia.

2021;23:1227–39. Article  CAS  Google Scholar  * Sun J, Zhou C, Zhao Y, Zhang X, Chen W, Zhou Q, 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  Google Scholar  * Lake DF, Faigel DO. The emerging role of QSOX1 in

cancer. Antioxid Redox Signal. 2014;21:485–96. Article  CAS  Google Scholar  * Xu MJ, Feng M. Radiation therapy in HCC: What Data Exist and What Data Do We Need to Incorporate into

Guidelines? Semin Liver Dis. 2019;39:43–52. Article  Google Scholar  * Yuan Y, Cao W, Zhou H, Qian H, Wang H. 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;110:859–71. Article  Google Scholar  * Fukui K, Yang Q, Cao Y, Takahashi N, Hatakeyama H,

Wang H, et al. The HNF-1 target collectrin controls insulin exocytosis by SNARE complex formation. Cell Metab. 2005;2:373–84. Article  CAS  Google Scholar  * Gao R, Kalathur RK,

Coto-Llerena M, Ercan C, Buechel D, Shuang S, et al. YAP/TAZ and ATF4 drive resistance to Sorafenib in hepatocellular carcinoma by preventing ferroptosis. EMBO Mol Med. 2021;13:e14351. * Fan

Z, Yang G, Zhang W, Liu Q, Liu G, Liu P, et al. Hypoxia blocks ferroptosis of hepatocellular carcinoma via suppression of METTL14 triggered YTHDF2‐dependent silencing of SLC7A11. J Cell Mol

Med. 2021;25:10197–212. Article  CAS  Google Scholar  * He L, Li H, Wu A, Peng Y, Shu G, Yin G. Functions of N6-methyladenosine and its role in cancer. Mol Cancer. 2019;18:1–15. Article 

CAS  Google Scholar  * Feng X, Wang S, Sun Z, Dong H, Yu H, Huang M, et al. Ferroptosis enhanced diabetic renal tubular injury via HIF-1α/HO-1 pathway in Db/Db mice. Front Endocrinol.

2021;12:21. Article  Google Scholar  * Miess H, Dankworth B, Gouw AM, Rosenfeldt M, Schmitz W, Jiang M, et al. The glutathione redox system is essential to prevent ferroptosis caused by

impaired lipid metabolism in clear cell renal cell carcinoma. Oncogene. 2018;37:5435–50. Article  CAS  Google Scholar  * Chen S, Zhao Y. Circular RNAs: characteristics, function, and role in

human cancer. Histol Histopathol. 2018;33:887–93. CAS  Google Scholar  * Gaffo E, Boldrin E, Dal Molin A, Bresolin S, Bonizzato A, Trentin L, et al. Circular RNA differential expression in

blood cell populations and exploration of circRNA deregulation in pediatric acute lymphoblastic leukemia. Sci Rep. 2019;9:1–12. Article  CAS  Google Scholar  * Xu Q, Zhou L, Yang G, Meng F,

Wan Y, Wang L, et al. CircIL4R facilitates the tumorigenesis and inhibits ferroptosis in hepatocellular carcinoma by regulating the miR‐541‐3p/GPX4 axis. Cell Biol Int. 2020;44:2344–56.

Article  CAS  Google Scholar  * Lyu N, Zeng Y, Kong Y, Chen Q, Deng H, Ou S, et al. Ferroptosis is involved in the progression of hepatocellular carcinoma through the

circ0097009/miR-1261/SLC7A11 axis. Ann Transl Med 2021;9:675. Article  Google Scholar  * Fang S, Chen W, Ding J, Zhang D, Zheng L, Song J, et al. Oxidative medicine and cellular longevity

Hsa_circ_0013731 mediated by E2F1 inhibits ferroptosis in hepatocellular carcinoma cells by sponging miR-877-3p and targeting SLC7A11. Researchsquare, 2021. * Qi W, Li Z, Xia L, Dai J, Zhang

Q, Wu C, et al. LncRNA GABPB1-AS1 and GABPB1 regulate oxidative stress during erastin-induced ferroptosis in HepG2 hepatocellular carcinoma cells. Sci Rep. 2019;9:1–12. Article  Google

Scholar  * Wong SL, Sukkar MB. The SPARC protein: an overview of its role in lung cancer and pulmonary fibrosis and its potential role in chronic airways disease. Br J Pharmacol.

2017;174:3–14. Article  CAS  Google Scholar  * Hua H-W, Jiang H-S, Jia L, Jia Y-P, Yao Y-L, Chen Y-W, et al. SPARC regulates ferroptosis induced by sorafenib in human hepatocellular

carcinoma. Cancer Biomark. 2021;32:425–33. * Dean M, Hamon Y, Chimini G. The human ATP-binding cassette (ABC) transporter superfamily. J lipid Res. 2001;42:1007–17. Article  CAS  Google

Scholar  * Ren J, Bi Y, Sowers JR, Hetz C, Zhang Y. Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases. Nat Rev Cardiol. 2021;18:499–521. Article  Google

Scholar  * Zheng X, Liu B, Liu X, Li P, Zhang P, Ye F, et al. PERK regulates the sensitivity of hepatocellular carcinoma cells to high-LET carbon ions via either apoptosis or ferroptosis. J

Cancer. 2022;13:669. Article  CAS  Google Scholar  * Ryskamp DA, Korban S, Zhemkov V, Kraskovskaya N, Bezprozvanny I. Neuronal sigma-1 receptors: signaling functions and protective roles in

neurodegenerative diseases. Front Neurosci. 2019;13:862. Article  Google Scholar  * Weng T-Y, Hung DT, Su T-P, Tsai S-YA. Loss of sigma-1 receptor chaperone promotes astrocytosis and

enhances the Nrf2 antioxidant defense. Oxid Med Cell Longev 2017;2017:4582135. Article  Google Scholar  * Bai T, Lei P, Zhou H, Liang R, Zhu R, Wang W, et al. Sigma-1 receptor protects

against ferroptosis in hepatocellular carcinoma cells. J Cell Mol Med. 2019;23:7349–59. Article  CAS  Google Scholar  * Roeser H, Lee G, Nacht S, Cartwright G. The role of ceruloplasmin in

iron metabolism. J Clin Investig. 1970;49:2408–17. Article  CAS  Google Scholar  * Shang Y, Luo M, Yao F, Wang S, Yuan Z, Yang Y. Ceruloplasmin suppresses ferroptosis by regulating iron

homeostasis in hepatocellular carcinoma cells. Cell Signal. 2020;72:109633. Article  CAS  Google Scholar  * Choudhury AD, Beltran H. Retinoblastoma loss in cancer: casting a wider net. Clin

Cancer Res. 2019;25:4199–201. Article  CAS  Google Scholar  * Louandre C, Marcq I, Bouhlal H, Lachaier E, Godin C, Saidak Z, et al. The retinoblastoma (Rb) protein regulates ferroptosis

induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett. 2015;356:971–7. Article  CAS  Google Scholar  * Kornberg A, Horecker B, Smyrniotis P. [42] Glucose-6-phosphate

dehydrogenase 6-phosphogluconic dehydrogenase. Methods in Enzymology Vol. 1, 323–327 (Academic Press, 1955). * Cao F, Luo A, Yang C. G6PD inhibits ferroptosis in hepatocellular carcinoma by

targeting cytochrome P450 oxidoreductase. Cell Signal. 2021;87:110098. Article  CAS  Google Scholar  * Shen Z-Q, Huang Y-L, Teng Y-C, Wang T-W, Kao C-H, Yeh C-H, et al. CISD2 maintains

cellular homeostasis. Biochimica et Biophysica Acta (BBA)-Molecular Cell Res. 2021;1868:118954. * Li B, Wei S, Yang L, Peng X, Ma Y, Wu B, et al. CISD2 promotes resistance to

sorafenib-induced ferroptosis by regulating autophagy in hepatocellular carcinoma. Front Oncol 2021;11:657723. Article  Google Scholar  * Yuan H, Li X, Zhang X, Kang R, Tang D. CISD1

inhibits ferroptosis by protection against mitochondrial lipid peroxidation. Biochem Biophys Res Commun. 2016;478:838–44. Article  CAS  Google Scholar  * Liu J, Song X, Kuang F, Zhang Q, Xie

Y, Kang R, et al. NUPR1 is a critical repressor of ferroptosis. Nat Commun. 2021;12:647. Article  CAS  Google Scholar  * Huang C, Santofimia-Castano P, Liu X, Xia Y, Peng L, Gotorbe C, et

al. NUPR1 inhibitor ZZW-115 induces ferroptosis in a mitochondria-dependent manner. Cell Death Discov. 2021;7:269. Article  CAS  Google Scholar  * Lu Y, Chan Y-T, Tan H-Y, Zhang C, Guo W, Xu

Y, et al. Epigenetic regulation of ferroptosis via ETS1/miR-23a-3p/ACSL4 axis mediates sorafenib resistance in human hepatocellular carcinoma. J Exp Clin Cancer Res. 2022;41:1–17. Article 

Google Scholar  * Ajoolabady A, Wang S, Kroemer G, Klionsky DJ, Uversky VN, Sowers JR, et al. ER stress in cardiometabolic diseases: from molecular mechanisms to therapeutics. Endocr Rev.

2021;42:839–71. Article  Google Scholar  * Liu Z, Ma C, Wang Q, Yang H, Lu Z, Bi T, et al. Targeting FAM134B-mediated reticulophagy activates sorafenib-induced ferroptosis in hepatocellular

carcinoma. Biochemical biophysical Res Commun. 2022;589:247–53. Article  CAS  Google Scholar  * Yang M, Wu X, Hu J, Wang Y, Wang Y, Zhang L, et al. COMMD10 inhibits HIF1α/CP loop to enhance

ferroptosis and radiosensitivity by disrupting Cu-Fe balance in hepatocellular carcinoma. J Hepatol. 2022;76:1138–50. Article  CAS  Google Scholar  * Chen Y, Li L, Lan J, Cui Y, Rao X, Zhao

J, et al. CRISPR screens uncover protective effect of PSTK as a regulator of chemotherapy-induced ferroptosis in hepatocellular carcinoma. Mol Cancer. 2022;21:1–17. Article  Google Scholar 

* Eling N, Reuter L, Hazin J, Hamacher-Brady A, Brady NR. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience. 2015;2:517. Article 

Google Scholar  * Li Z-J, Dai H-Q, Huang X-W, Feng J, Deng J-H, Wang Z-X, et al. Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacologica

Sin. 2021;42:301–10. Article  CAS  Google Scholar  * Kotawong K, Chaijaroenkul W, Muhamad P, Na-Bangchang K. Cytotoxic activities and effects of atractylodin and β-eudesmol on the cell cycle

arrest and apoptosis on cholangiocarcinoma cell line. J Pharmacol Sci. 2018;136:51–56. Article  CAS  Google Scholar  * He Y, Fang D, Liang T, Pang H, Nong Y, Tang L, et al. Atractylodin may

induce ferroptosis of human hepatocellular carcinoma cells. Ann Transl Med 2021;9:1535. Article  CAS  Google Scholar  * Yin L, Shi C, Zhang Z, Wang W, Li M. Formosanin C attenuates

lipopolysaccharide-induced inflammation through nuclear factor-κB inhibition in macrophages. Korean J Physiol Pharmacol. 2021;25:395–401. Article  CAS  Google Scholar  * Su C-L, Lin P-L.

Natural saponin formosanin c‐induced ferroptosis in human hepatocellular carcinoma cells involved ferritinophagy. FASEB J. 2020;34:1–1. CAS  Google Scholar  * Lin P-L, Tang H-H, Wu S-Y, Shaw

N-S, Su C-L. Saponin formosanin C-induced ferritinophagy and ferroptosis in human hepatocellular carcinoma cells. Antioxidants. 2020;9:682. Article  CAS  Google Scholar  * Irving CB, Adams

CE, Lawrie S. Haloperidol versus placebo for schizophrenia. The Cochrane database of systematic reviews. 2013;Cd003082. https://doi.org/10.1002/14651858.CD003082.pub3. * Bai T, Wang S, Zhao

Y, Zhu R, Wang W, Sun Y. Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells. Biochemical Biophysical Res Commun. 2017;491:919–25. Article  CAS

  Google Scholar  * Schumacher M, Cerella C, Eifes S, Chateauvieux S, Morceau F, Jaspars M, et al. Heteronemin, a spongean sesterterpene, inhibits TNFα-induced NF-κB activation through

proteasome inhibition and induces apoptotic cell death. Biochemical Pharmacol. 2010;79:610–22. Article  CAS  Google Scholar  * Ren X, Li Y, Zhou Y, Hu W, Yang C, Jing Q, et al. Overcoming

the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis. Redox Biol. 2021;46:102122. Article  CAS  Google Scholar 

* Markossian S, Ang KK, Wilson CG, Arkin MR. Small-molecule screening for genetic diseases. Annu Rev Genomics Hum Genet. 2018;19:263–88. Article  CAS  Google Scholar  * Bollong MJ, Yun H,

Sherwood L, Woods AK, Lairson LL, Schultz PG. A small molecule inhibits deregulated NRF2 transcriptional activity in cancer. ACS Chem Biol. 2015;10:2193–8. Article  CAS  Google Scholar  *

Singh A, Venkannagari S, Oh KH, Zhang Y-Q, Rohde JM, Liu L, et al. Small molecule inhibitor of NRF2 selectively intervenes therapeutic resistance in KEAP1-deficient NSCLC tumors. ACS Chem

Biol. 2016;11:3214–25. Article  CAS  Google Scholar  * Matthews JH, Liang X, Paul VJ, Luesch H. A complementary chemical and genomic screening approach for druggable targets in the Nrf2

pathway and small molecule inhibitors to overcome cancer cell drug resistance. ACS Chem Biol. 2018;13:1189–99. Article  CAS  Google Scholar  * Gao L, Xue J, Liu X, Cao L, Wang R, Lei L. A

scoring model based on ferroptosis genes for prognosis and immunotherapy response prediction and tumor microenvironment evaluation in liver hepatocellular carcinoma. Aging. 2021;13:24866.

Article  CAS  Google Scholar  * Deng T, Hu B, Jin C, Tong Y, Zhao J, Shi Z, et al. A novel ferroptosis phenotype-related clinical-molecular prognostic signature for hepatocellular carcinoma.

J Cell Mol Med. 2021;25:6618–33. Article  CAS  Google Scholar  * Chen Z-A, Tian H, Yao D-M, Zhang Y, Feng Z-J, Yang C-J. Identification of a ferroptosis-related signature model including

mRNAs and lncRNAs for predicting prognosis and immune activity in hepatocellular carcinoma. Front Oncol 2021;11:738477. Article  Google Scholar  * Chen X, Kang R, Kroemer G, Tang D.

Ferroptosis in infection, inflammation, and immunity. J Exp Med. 2021;218:e20210518. * Chen X, Comish P, Tang D, Kang R. Characteristics and biomarkers of ferroptosis. Front. Cell Dev. Biol.

2021; https://doi.org/10.3389/fcell.2021.637162. * Rodriguez R, Schreiber SL, Conrad M. Persister cancer cells: iron addiction and vulnerability to ferroptosis. Mol Cell. 2021;

https://doi.org/10.1016/j.molcel.2021.12.001. * Yuk H, Abdullah M, Kim D-H, Lee H, Lee S-J. Necrostatin-1 prevents ferroptosis in a RIPK1-and IDO-independent manner in hepatocellular

carcinoma. Antioxidants. 2021;10:1347. Article  CAS  Google Scholar  * Jin M, Shi C, Li T, Wu Y, Hu C, Huang G. Solasonine promotes ferroptosis of hepatoma carcinoma cells via glutathione

peroxidase 4-induced destruction of the glutathione redox system. Biomedicine Pharmacother. 2020;129:110282. Article  CAS  Google Scholar  * Zhang P, Liu C, Wu W, Mao Y, Qin Y, Hu J, et al.

Triapine/Ce6-loaded and lactose-decorated nanomicelles provide an effective chemo-photodynamic therapy for hepatocellular carcinoma through a reactive oxygen species-boosting and

ferroptosis-inducing mechanism. Chem Eng J. 2021;425:131543. Article  CAS  Google Scholar  * Chen H, Zhang W, Zhu G, Xie J, Chen X. Rethinking cancer nanotheranostics. Nat Rev Mater.

2017;2:1–18. Article  CAS  Google Scholar  * Dai Y, Xu C, Sun X, Chen X. Nanoparticle design strategies for enhanced anticancer therapy by exploiting the tumour microenvironment. Chem Soc

Rev. 2017;46:3830–52. Article  CAS  Google Scholar  * Cai Y, Wei Z, Song C, Tang C, Han W, Dong X. Optical nano-agents in the second near-infrared window for biomedical applications. Chem

Soc Rev. 2019;48:22–37. Article  CAS  Google Scholar  * Liang P, Huang X, Wang Y, Chen D, Ou C, Zhang Q, et al. Tumor-microenvironment-responsive nanoconjugate for synergistic antivascular

activity and phototherapy. ACS Nano. 2018;12:11446–57. Article  CAS  Google Scholar  * Shen Z, Song J, Yung BC, Zhou Z, Wu A, Chen X. Emerging strategies of cancer therapy based on

ferroptosis. Adv Mater. 2018;30:1704007. Article  Google Scholar  * Liu M, Liu B, Liu Q, Du K, Wang Z, He N. Nanomaterial-induced ferroptosis for cancer specific therapy. Coord Chem Rev.

2019;382:160–80. Article  CAS  Google Scholar  * Zhang Y, Tan H, Daniels JD, Zandkarimi F, Liu H, Brown LM, et al. Imidazole ketone erastin induces ferroptosis and slows tumor growth in a

mouse lymphoma model. Cell Chem Biol. 2019;26:623–33. e629. Article  CAS  Google Scholar  * Liang C, Zhang X, Yang M, Dong X. Recent progress in ferroptosis inducers for cancer therapy. Adv

Mater. 2019;31:1904197. Article  CAS  Google Scholar  * Boland P, Wu J. Systemic therapy for hepatocellular carcinoma: beyond sorafenib. Chin Clin Oncol. 2018;7:50–50. Article  Google

Scholar  * Yue H, Gou L, Tang Z, Liu Y, Liu S, Tang H. Construction of pH-responsive nanocarriers in combination with ferroptosis and chemotherapy for treatment of hepatocellular carcinoma.

Cancer Nanotechnol. 2022;13:1–21. Article  Google Scholar  * Tang H, Chen D, Li C, Zheng C, Wu X, Zhang Y, et al. Dual GSH-exhausting sorafenib loaded manganese-silica nanodrugs for inducing

the ferroptosis of hepatocellular carcinoma cells. Int J Pharmaceutics. 2019;572:118782. Article  CAS  Google Scholar  Download references ACKNOWLEDGEMENTS The authors wish to express our

sincere apology to those authors whose important work cannot be discussed and cited due to page limitations. GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence

National de la Recherche (ANR)—Projets blancs; AMMICa US23/CNRS UMS3655; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale

(FRM); a donation by Elior; Equipex Onco-Pheno-Screen; European Joint Programme on Rare Diseases (EJPRD); Gustave Roussy Odyssea, the European Union Horizon 2020 Projects Oncobiome and

Crimson; Fondation Carrefour; Institut National du Cancer (INCa); Institut Universitaire de France; LabEx Immuno-Oncology (ANR-18-IDEX-0001); a Cancer Research ASPIRE Award from the Mark

Foundation; the RHU Immunolife; Seerave Foundation; SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); and SIRIC Cancer Research and Personalised Medicine

(CARPEM). This study contributes to the IdEx Université de Paris ANR-18-IDEX-0001. FUNDING Not applicable. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Shanghai Institute of Cardiovascular

Diseases, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, China Amir Ajoolabady & Jun Ren * Department of Surgery, UT Southwestern Medical Center, Dallas, TX,

75390, USA Daolin Tang * Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, Inserm U1138, Institut Universitaire

de France, Paris, France Guido Kroemer * Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France Guido Kroemer * Pôle de Biologie, Hôpital Européen Georges

Pompidou, AP-HP, Paris, France Guido Kroemer Authors * Amir Ajoolabady View author publications You can also search for this author inPubMed Google Scholar * Daolin Tang View author

publications You can also search for this author inPubMed Google Scholar * Guido Kroemer View author publications You can also search for this author inPubMed Google Scholar * Jun Ren View

author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS AA has written the initial draft of the manuscript, and DT, GK and JR have contributed to the

revising, editing and finalising of the manuscript. CORRESPONDING AUTHORS Correspondence to Daolin Tang, Guido Kroemer or Jun Ren. ETHICS DECLARATIONS ETHICS APPROVAL AND CONSENT TO

PARTICIPATE Not applicable. CONSENT TO PUBLISH Not applicable. COMPETING INTERESTS GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar,

Samsara, Sanofi, Sotio, Tollys, Vascage and Vasculox/Tioma. GK has been consulting for Reithera. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a

scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is the inventor of patents covering therapeutic targeting of ageing, cancer, cystic

fibrosis and metabolic disorders. The remaining authors declare no competing interests. ADDITIONAL INFORMATION PUBLISHER’S NOTE Springer Nature remains neutral with regard to jurisdictional

claims in published maps and institutional affiliations. GLOSSARY * Autophagy An evolutionarily conserved process in eukaryote cells mediating engulfment of damaged organelles or cellular

components within transitory organelles, so-called, autophagosomes, which subsequently fuse with lysosomes for ultimate degradation of the engulfed cargo. * Cathepsin B/L Cathepsin B/L are

lysosomal cysteine proteases playing a role in cellular functions, including intracellular proteolysis. * Chronic hepatitis Refers to liver inflammation and impairment inflicted by hepatitis

B and C viruses and drug toxicity. * Ferrireductases A group of enzymes that mediate the reduction of Fe3+ to Fe2+. * Hemochromatosis A disorder caused by accumulation and build-up of extra

iron in the body. * Methylome A technique analysing the distribution of 5-methylcytosine in the entire genome. * Myristoylation A lipid modification mechanism in which a fatty acid known as

myristic acid binds to the N-terminal domain of a protein. * Non-alcoholic steatohepatitis (NASH) Refers to liver inflammation and impairment induced by fat accumulation in the liver. *

Saponin Natural glycosides, which constitute sugars like apiose, arabinose, galactose, and glucose, are found abundantly in plants. * Transcriptome Refers to a thorough range/record of

expressed mRNAs within an organism. * Xenobiotics Refers to chemical compounds that are naturally produced or exists within an organism. RIGHTS AND PERMISSIONS Springer Nature or its

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article is solely governed by the terms of such publishing agreement and applicable law. Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Ajoolabady, A., Tang, D., Kroemer, G.

_et al._ Ferroptosis in hepatocellular carcinoma: mechanisms and targeted therapy. _Br J Cancer_ 128, 190–205 (2023). https://doi.org/10.1038/s41416-022-01998-x Download citation * Received:

29 April 2022 * Revised: 25 August 2022 * Accepted: 22 September 2022 * Published: 13 October 2022 * Issue Date: 19 January 2023 * DOI: https://doi.org/10.1038/s41416-022-01998-x SHARE THIS

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