Research status and prospects of ferroptosis in hepatocellular carcinoma and its drug resistance_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Weizhi ,  LIU Lianxin

Department of Liver Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin 150001, P. R. China;

Corresponding author：

LIU Lianxin, Email: liulx@ustc.edu.cn

Keywords：

ferroptosis; hepatocellular carcinoma; lipid peroxidation; sorafenib; resistance mechanism

DOI：

10.7507/1007-9424.202106100

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To summarize the papers about the research status and prospects of ferroptosis in hepatocellular carcinoma (HCC) and its drug resistance in recent years in order to provide directions and ideas for the treatment of HCC. Method The relevant literatures at home and abroad in recent years about ferroptosis in HCC and its drug resistance were reviewed. Results The mechanism of ferroptosis in the development and drug resistance of HCC was complicated, involving multiple protein and molecular pathways. Ferroptosis played an important role in improving chemotherapy and sorafenib resistance, and it had a broad application prospect in HCC. Conclusions The molecular mechanism of ferroptosis in HCC and its drug resistance has not been fully elucidated. Further research on the mechanism of ferroptosis in HCC may provide new molecular therapeutic targets for HCC. Ferroptosis has a broad application prospect in the treatment of HCC.

Citation： ZHANG Weizhi, LIU Lianxin. Research status and prospects of ferroptosis in hepatocellular carcinoma and its drug resistance. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(5): 694-700. doi: 10.7507/1007-9424.202106100 Copy

1.	Galluzzi L, Bravo-San Pedro JM, Vitale I, et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ, 2015, 22(1): 58-73.
2.	Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.
3.	Hentze MW, Muckenthaler MU, Galy B, et al. Two to tango: regulation of mammalian iron metabolism. Cell, 2010, 142(1): 24-38.
4.	Shen Z, Liu T, Li Y, et al. Fenton-reaction-acceleratable magnetic nanoparticles for ferroptosis therapy of orthotopic brain tumors. ACS Nano, 2018, 12(11): 11355-11365.
5.	中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范(2019年版). 中国实用外科杂志, 2020, 40(2): 121-138.
6.	Dimri M, Satyanarayana A. Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma. Cancers (Basel), 2020, 12(2): 491. doi: 10.3390/cancers12020491.
7.	Schwabe RF, Luedde T. Apoptosis and necroptosis in the liver: a matter of life and death. Nat Rev Gastroenterol Hepatol, 2018, 15(12): 738-752.
8.	Gong Y, Fan Z, Luo G, et al. The role of necroptosis in cancer biology and therapy. Mol Cancer, 2019, 18(1): 100. doi: 10.1186/s12943-019-1029-8.
9.	Allaire M, Rautou PE, Codogno P, et al. Autophagy in liver diseases: Time for translation? J Hepatol, 2019, 70(5): 985-998.
10.	Miotto G, Rossetto M, Di Paolo ML, et al. Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol, 2020, 28: 101328. doi: 10.1016/j.redox.2019.101328.
11.	Louandre C, Marcq I, Bouhlal H, et al. The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett, 2015, 356(2PtB): 971-977.
12.	Wang J, Shanmugam A, Markand S, et al. Sigma 1 receptor regulates the oxidative stress response in primary retinal Müller glial cells via NRF2 signaling and system xc^-, the Na⁺-independent glutamate-cystine exchanger. Free Radic Biol Med, 2015, 86: 25-36.
13.	Pal A, Fontanilla D, Gopalakrishnan A, et al. The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements. Eur J Pharmacol, 2012, 682(1-3): 12-20.
14.	Bai T, Lei P, Zhou H, et al. Sigma-1 receptor protects against ferroptosis in hepatocellular carcinoma cells. J Cell Mol Med, 2019, 23(11): 7349-7359.
15.	Patel SJ, Frey AG, Palenchar DJ, et al. A PCBP1-BolA2 chaperone complex delivers iron for cytosolic [2Fe-2S] cluster assembly. Nat Chem Biol, 2019, 15(9): 872-881.
16.	Protchenko O, Baratz E, Jadhav S, et al. Iron chaperone poly rC binding protein 1 protects mouse liver from lipid peroxidation and steatosis. Hepatology, 2021, 73(3): 1176-1193.
17.	Zhang J, Zhang X, Li J, et al. Systematic analysis of the ABC transporter family in hepatocellular carcinoma reveals the importance of ABCB6 in regulating ferroptosis. Life Sci, 2020, 257: 118131. doi: 10.1016/j.lfs.2020.118131.
18.	Yuan H, Li X, Zhang X, et al. CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation. Biochem Biophys Res Commun, 2016, 478(2): 838-844.
19.	Wang L, Cai H, Hu Y, et al. A pharmacological probe identifies cystathionine β-synthase as a new negative regulator for ferroptosis. Cell Death Dis, 2018, 9(10): 1005. doi: 10.1038/s41419-018-1063-2.
20.	Yang Y, Lin J, Guo S, et al. RRM2 protects against ferroptosis and is a tumor biomarker for liver cancer. Cancer Cell Int, 2020, 20(1): 587. doi: 10.1186/s12935-020-01689-8.
21.	Wang Q, Guo Y, Wang W, et al. RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA. Exp Cell Res, 2021, 399(1): 112453. doi: 10.1016/j.yexcr.2020.112453.
22.	Dai C, Chen X, Li J, et al. Transcription factors in ferroptotic cell death. Cancer Gene Ther, 2020, 27(9): 645-656.
23.	Bai T, Wang S, Zhao Y, et al. Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells. Biochem Biophys Res Commun, 2017, 491(4): 919-925.
24.	Ou W, Mulik RS, Anwar A, et al. Low-density lipoprotein docosahexaenoic acid nanoparticles induce ferroptotic cell death in hepatocellular carcinoma. Free Radic Biol Med, 2017, 112: 597-607.
25.	Tang H, Chen D, Li C, et al. Dual GSH-exhausting sorafenib loaded manganese-silica nanodrugs for inducing the ferroptosis of hepatocellular carcinoma cells. Int J Pharm, 2019, 572: 118782. doi: 10.1016/j.ijpharm.2019.118782.
26.	Qi W, Li Z, Xia L, et al. LncRNA GABPB1-AS1 and GABPB1 regulate oxidative stress during erastin-induced ferroptosis in HepG2 hepatocellular carcinoma cells. Sci Rep, 2019, 9(1): 16185. doi: 10.1038/s41598-019-52837-8.
27.	Orso F, Quirico L, Dettori D, et al. Role of miRNAs in tumor and endothelial cell interactions during tumor progression. Semin Cancer Biol, 2020, 60: 214-224.
28.	Bai T, Liang R, Zhu R, et al. MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells. J Cell Physiol, 2020, 235(7-8): 5637-5648.
29.	Babu KR, Muckenthaler MU. miR-148a regulates expression of the transferrin receptor 1 in hepatocellular carcinoma. Sci Rep, 2019, 9(1): 1518. doi: 10.1038/s41598-018-35947-7.
30.	Xu Q, Zhou L, Yang G, 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(11): 2344-2356.
31.	Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature, 2015, 520(7545): 57-62.
32.	Ou Y, Wang SJ, Li D, et al. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc Natl Acad Sci U S A, 2016, 113(44): E6806-E6812. doi: 10.1073/pnas.1607152113.
33.	Xie Y, Zhu S, Song X, et al. The Tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep, 2017, 20(7): 1692-1704.
34.	Leu JI, Murphy ME, George DL. Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53. Proc Natl Acad Sci U S A, 2019, 116(17): 8390-8396.
35.	Sun X, Ou Z, Chen R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology, 2016, 63(1): 173-184.
36.	Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature, 2019, 575(7782): 299-309.
37.	Oikawa T. Cancer Stem cells and their cellular origins in primary liver and biliary tract cancers. Hepatology, 2016, 64(2): 645-651.
38.	Yang L, Shi P, Zhao G, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther, 2020, 5(1): 8. doi: 10.1038/s41392-020-0110-5.
39.	Friedmann Angeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer, 2019, 19(7): 405-414.
40.	Taylor WR, Fedorka SR, Gad I, et al. Small-molecule ferroptotic agents with potential to selectively target cancer stem cells. Sci Rep, 2019, 9(1): 5926. doi: 10.1038/s41598-019-42251-5.
41.	Hata AN, Niederst MJ, Archibald HL, et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med, 2016, 22(3): 262-269.
42.	Jiang M, Qiao M, Zhao C, et al. Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers. Transl Lung Cancer Res, 2020, 9(4): 1569-1584.
43.	Hangauer MJ, Viswanathan VS, Ryan MJ, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature, 2017, 551(7679): 247-250.
44.	Sun X, Niu X, Chen R, et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology, 2016, 64(2): 488-500.
45.	Louandre C, Ezzoukhry Z, Godin C, et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int J Cancer, 2013, 133(7): 1732-1742.
46.	Sehm T, Rauh M, Wiendieck K, et al. Temozolomide toxicity operates in a xCT/SLC7a11 dependent manner and is fostered by ferroptosis. Oncotarget, 2016, 7(46): 74630-74647.
47.	Wu J, Minikes AM, Gao M, et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature, 2019, 572(7769): 402-406.
48.	Lin PL, Tang HH, Wu SY, et al. Saponin formosanin C-induced ferritinophagy and ferroptosis in human hepatocellular carcinoma cells. Antioxidants (Basel), 2020, 9(8): 682. doi: 10.3390/antiox9080682.
49.	Xiong Y, Xiao C, Li Z, et al. Engineering nanomedicine for glutathione depletion-augmented cancer therapy. Chem Soc Rev, 2021, 50(10): 6013-6041.
50.	Lippmann J, Petri K, Fulda S, et al. Redox modulation and induction of ferroptosis as a new therapeutic strategy in hepatocellular carcinoma. Transl Oncol, 2020, 13(8): 100785. doi: 10.1016/j.tranon.2020.100785.
51.	Wang W, Green M, Choi JE, et al. CD8⁺ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature, 2019, 569(7755): 270-274.
52.	Deng T, Hu B, Jin C, et al. A novel ferroptosis phenotype-related clinical-molecular prognostic signature for hepatocellular carcinoma. J Cell Mol Med, 2021, 25(14): 6618-6633.
53.	Liu Z, Wang L, Liu L, 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. doi: 10.3389/fonc.2021.619242.
54.	Liang JY, Wang DS, Lin HC, 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.
55.	Du X, Zhang Y. Integrated analysis of immunity- and ferroptosis-related biomarker signatures to improve the prognosis prediction of hepatocellular carcinoma. Front Genet, 2020, 11: 614888. doi: 10.3389/fgene.2020.614888.

1. Galluzzi L, Bravo-San Pedro JM, Vitale I, et al. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015. Cell Death Differ, 2015, 22(1): 58-73.
2. Dixon SJ, Lemberg KM, Lamprecht MR, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell, 2012, 149(5): 1060-1072.
3. Hentze MW, Muckenthaler MU, Galy B, et al. Two to tango: regulation of mammalian iron metabolism. Cell, 2010, 142(1): 24-38.
4. Shen Z, Liu T, Li Y, et al. Fenton-reaction-acceleratable magnetic nanoparticles for ferroptosis therapy of orthotopic brain tumors. ACS Nano, 2018, 12(11): 11355-11365.
5. 中华人民共和国国家卫生健康委员会医政医管局. 原发性肝癌诊疗规范(2019年版). 中国实用外科杂志, 2020, 40(2): 121-138.
6. Dimri M, Satyanarayana A. Molecular signaling pathways and therapeutic targets in hepatocellular carcinoma. Cancers (Basel), 2020, 12(2): 491. doi: 10.3390/cancers12020491.
7. Schwabe RF, Luedde T. Apoptosis and necroptosis in the liver: a matter of life and death. Nat Rev Gastroenterol Hepatol, 2018, 15(12): 738-752.
8. Gong Y, Fan Z, Luo G, et al. The role of necroptosis in cancer biology and therapy. Mol Cancer, 2019, 18(1): 100. doi: 10.1186/s12943-019-1029-8.
9. Allaire M, Rautou PE, Codogno P, et al. Autophagy in liver diseases: Time for translation? J Hepatol, 2019, 70(5): 985-998.
10. Miotto G, Rossetto M, Di Paolo ML, et al. Insight into the mechanism of ferroptosis inhibition by ferrostatin-1. Redox Biol, 2020, 28: 101328. doi: 10.1016/j.redox.2019.101328.
11. Louandre C, Marcq I, Bouhlal H, et al. The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett, 2015, 356(2PtB): 971-977.
12. Wang J, Shanmugam A, Markand S, et al. Sigma 1 receptor regulates the oxidative stress response in primary retinal Müller glial cells via NRF2 signaling and system xc^-, the Na⁺-independent glutamate-cystine exchanger. Free Radic Biol Med, 2015, 86: 25-36.
13. Pal A, Fontanilla D, Gopalakrishnan A, et al. The sigma-1 receptor protects against cellular oxidative stress and activates antioxidant response elements. Eur J Pharmacol, 2012, 682(1-3): 12-20.
14. Bai T, Lei P, Zhou H, et al. Sigma-1 receptor protects against ferroptosis in hepatocellular carcinoma cells. J Cell Mol Med, 2019, 23(11): 7349-7359.
15. Patel SJ, Frey AG, Palenchar DJ, et al. A PCBP1-BolA2 chaperone complex delivers iron for cytosolic [2Fe-2S] cluster assembly. Nat Chem Biol, 2019, 15(9): 872-881.
16. Protchenko O, Baratz E, Jadhav S, et al. Iron chaperone poly rC binding protein 1 protects mouse liver from lipid peroxidation and steatosis. Hepatology, 2021, 73(3): 1176-1193.
17. Zhang J, Zhang X, Li J, et al. Systematic analysis of the ABC transporter family in hepatocellular carcinoma reveals the importance of ABCB6 in regulating ferroptosis. Life Sci, 2020, 257: 118131. doi: 10.1016/j.lfs.2020.118131.
18. Yuan H, Li X, Zhang X, et al. CISD1 inhibits ferroptosis by protection against mitochondrial lipid peroxidation. Biochem Biophys Res Commun, 2016, 478(2): 838-844.
19. Wang L, Cai H, Hu Y, et al. A pharmacological probe identifies cystathionine β-synthase as a new negative regulator for ferroptosis. Cell Death Dis, 2018, 9(10): 1005. doi: 10.1038/s41419-018-1063-2.
20. Yang Y, Lin J, Guo S, et al. RRM2 protects against ferroptosis and is a tumor biomarker for liver cancer. Cancer Cell Int, 2020, 20(1): 587. doi: 10.1186/s12935-020-01689-8.
21. Wang Q, Guo Y, Wang W, et al. RNA binding protein DAZAP1 promotes HCC progression and regulates ferroptosis by interacting with SLC7A11 mRNA. Exp Cell Res, 2021, 399(1): 112453. doi: 10.1016/j.yexcr.2020.112453.
22. Dai C, Chen X, Li J, et al. Transcription factors in ferroptotic cell death. Cancer Gene Ther, 2020, 27(9): 645-656.
23. Bai T, Wang S, Zhao Y, et al. Haloperidol, a sigma receptor 1 antagonist, promotes ferroptosis in hepatocellular carcinoma cells. Biochem Biophys Res Commun, 2017, 491(4): 919-925.
24. Ou W, Mulik RS, Anwar A, et al. Low-density lipoprotein docosahexaenoic acid nanoparticles induce ferroptotic cell death in hepatocellular carcinoma. Free Radic Biol Med, 2017, 112: 597-607.
25. Tang H, Chen D, Li C, et al. Dual GSH-exhausting sorafenib loaded manganese-silica nanodrugs for inducing the ferroptosis of hepatocellular carcinoma cells. Int J Pharm, 2019, 572: 118782. doi: 10.1016/j.ijpharm.2019.118782.
26. Qi W, Li Z, Xia L, et al. LncRNA GABPB1-AS1 and GABPB1 regulate oxidative stress during erastin-induced ferroptosis in HepG2 hepatocellular carcinoma cells. Sci Rep, 2019, 9(1): 16185. doi: 10.1038/s41598-019-52837-8.
27. Orso F, Quirico L, Dettori D, et al. Role of miRNAs in tumor and endothelial cell interactions during tumor progression. Semin Cancer Biol, 2020, 60: 214-224.
28. Bai T, Liang R, Zhu R, et al. MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells. J Cell Physiol, 2020, 235(7-8): 5637-5648.
29. Babu KR, Muckenthaler MU. miR-148a regulates expression of the transferrin receptor 1 in hepatocellular carcinoma. Sci Rep, 2019, 9(1): 1518. doi: 10.1038/s41598-018-35947-7.
30. Xu Q, Zhou L, Yang G, 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(11): 2344-2356.
31. Jiang L, Kon N, Li T, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature, 2015, 520(7545): 57-62.
32. Ou Y, Wang SJ, Li D, et al. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc Natl Acad Sci U S A, 2016, 113(44): E6806-E6812. doi: 10.1073/pnas.1607152113.
33. Xie Y, Zhu S, Song X, et al. The Tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep, 2017, 20(7): 1692-1704.
34. Leu JI, Murphy ME, George DL. Mechanistic basis for impaired ferroptosis in cells expressing the African-centric S47 variant of p53. Proc Natl Acad Sci U S A, 2019, 116(17): 8390-8396.
35. Sun X, Ou Z, Chen R, et al. Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology, 2016, 63(1): 173-184.
36. Vasan N, Baselga J, Hyman DM. A view on drug resistance in cancer. Nature, 2019, 575(7782): 299-309.
37. Oikawa T. Cancer Stem cells and their cellular origins in primary liver and biliary tract cancers. Hepatology, 2016, 64(2): 645-651.
38. Yang L, Shi P, Zhao G, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther, 2020, 5(1): 8. doi: 10.1038/s41392-020-0110-5.
39. Friedmann Angeli JP, Krysko DV, Conrad M. Ferroptosis at the crossroads of cancer-acquired drug resistance and immune evasion. Nat Rev Cancer, 2019, 19(7): 405-414.
40. Taylor WR, Fedorka SR, Gad I, et al. Small-molecule ferroptotic agents with potential to selectively target cancer stem cells. Sci Rep, 2019, 9(1): 5926. doi: 10.1038/s41598-019-42251-5.
41. Hata AN, Niederst MJ, Archibald HL, et al. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Nat Med, 2016, 22(3): 262-269.
42. Jiang M, Qiao M, Zhao C, et al. Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers. Transl Lung Cancer Res, 2020, 9(4): 1569-1584.
43. Hangauer MJ, Viswanathan VS, Ryan MJ, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature, 2017, 551(7679): 247-250.
44. Sun X, Niu X, Chen R, et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology, 2016, 64(2): 488-500.
45. Louandre C, Ezzoukhry Z, Godin C, et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int J Cancer, 2013, 133(7): 1732-1742.
46. Sehm T, Rauh M, Wiendieck K, et al. Temozolomide toxicity operates in a xCT/SLC7a11 dependent manner and is fostered by ferroptosis. Oncotarget, 2016, 7(46): 74630-74647.
47. Wu J, Minikes AM, Gao M, et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature, 2019, 572(7769): 402-406.
48. Lin PL, Tang HH, Wu SY, et al. Saponin formosanin C-induced ferritinophagy and ferroptosis in human hepatocellular carcinoma cells. Antioxidants (Basel), 2020, 9(8): 682. doi: 10.3390/antiox9080682.
49. Xiong Y, Xiao C, Li Z, et al. Engineering nanomedicine for glutathione depletion-augmented cancer therapy. Chem Soc Rev, 2021, 50(10): 6013-6041.
50. Lippmann J, Petri K, Fulda S, et al. Redox modulation and induction of ferroptosis as a new therapeutic strategy in hepatocellular carcinoma. Transl Oncol, 2020, 13(8): 100785. doi: 10.1016/j.tranon.2020.100785.
51. Wang W, Green M, Choi JE, et al. CD8⁺ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature, 2019, 569(7755): 270-274.
52. Deng T, Hu B, Jin C, et al. A novel ferroptosis phenotype-related clinical-molecular prognostic signature for hepatocellular carcinoma. J Cell Mol Med, 2021, 25(14): 6618-6633.
53. Liu Z, Wang L, Liu L, 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. doi: 10.3389/fonc.2021.619242.
54. Liang JY, Wang DS, Lin HC, 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.
55. Du X, Zhang Y. Integrated analysis of immunity- and ferroptosis-related biomarker signatures to improve the prognosis prediction of hepatocellular carcinoma. Front Genet, 2020, 11: 614888. doi: 10.3389/fgene.2020.614888.

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