Welcome to Francis Academic Press

Frontiers in Medical Science Research, 2026, 8(4); doi: 10.25236/FMSR.2026.080401.

Research Progress on Ferroptosis in the Occurrence, Development and Treatment of Hepatocellular Carcinoma

Author(s)

Xinlian Zhang1, Tao Peng2

Corresponding Author:
Tao Peng
Affiliation(s)

1The First People's Hospital Affiliated to Yangtze University, Jingzhou, Hubei, China

2Jingzhou First People's Hospital, Jingzhou, Hubei, China

Abstract

Hepatocellular carcinoma (HCC) is [1]the most common and most lethal primary liver cancer globally, characterized by complex pathogenesis, difficult early diagnosis, frequent therapeutic resistance, and poor overall prognosis. As a novel iron-dependent form of programmed cell death, ferroptosis has attracted extensive attention in the field of tumor biology in recent years. This paper systematically summarizes the molecular regulatory mechanisms of ferroptosis in HCC, including abnormal alterations in core pathways such as iron metabolism, lipid peroxidation, and glutathione peroxidase 4 (GPX4), as well as its regulatory effects on tumor proliferation, metastasis, and the immune microenvironment. Meanwhile, this review focuses on the potential value of ferroptosis in reversing therapeutic resistance in HCC. In addition, this paper also summarizes the application prospects of ferroptosis-related gene-based biomarkers in the diagnosis and prognostic evaluation of HCC, as well as the latest research progress of ferroptosis-targeting therapeutic strategies (such as GPX4 inhibitors, system xc⁻ inhibitors, iron nanomedicines, etc.), providing new ideas and potential intervention targets for the precise treatment of HCC.

Keywords

Hepatocellular Carcinoma; Ferroptosis; Lipid Peroxidation; GPX4; Targeted Therapy

Cite This Paper

Xinlian Zhang, Tao Peng. Research Progress on Ferroptosis in the Occurrence, Development and Treatment of Hepatocellular Carcinoma. Frontiers in Medical Science Research (2026), Vol. 8, Issue 4: 1-7. https://doi.org/10.25236/FMSR.2026.080401.

References

[1] Zou Y, Wan X, Zhou Q, et al. Mechanisms of drug resistance in hepatocellular carcinoma[J]. Biol Proced Online, 2025, 27(1): 19.

[2] Ajoolabady A, Tang D, Kroemer G, Ren J. Ferroptosis in hepatocellular carcinoma: mechanisms and targeted therapy. Br J Cancer. 2023 Jan;128(2):190-205.

[3] Zhu X, Sha X, Zang Y, et al. Current progress of ferroptosis study in hepatocellular carcinoma[J]. Int J Biol Sci, 2024, 20(9): 3621-3637.

[4] Nie J, Lin B, Zhou M, et al. Role of ferroptosis in hepatocellular carcinoma[J]. J Cancer Res Clin Oncol, 2018, 144(12): 2329-2337.

[5] Jiang S, Zhang G, Ma Y, et al. Ferroptosis in hepatocellular carcinoma, from mechanism to effect[J]. Front Oncol, 2024, 14: 1350011.

[6] Zhou Q, Meng Y, Li D, et al. Ferroptosis in cancer: From molecular mechanisms to therapeutic strategies[J]. Signal Transduct Target Ther, 2024, 9(1): 55.

[7] Huang J, Zhao Y, Luo X, et al. Dexmedetomidine inhibits ferroptosis and attenuates sepsis-induced acute kidney injury via activating the Nrf2/SLC7A11/FSP1/CoQ10 pathway[J]. Redox Rep, 2024, 29(1): 2430929.

[8] Vogt AS, Arsiwala T, Mohsen M, Vogel M, Manolova V, Bachmann MF. On Iron Metabolism and Its Regulation. Int J Mol Sci. 2021 Apr 27;22(9):4591.

[9] Yu H, Guo P, Xie X, et al. Ferroptosis, a new form of cell death, and its relationships with tumourous diseases[J]. J Cell Mol Med, 2017, 21(4): 648-657.

[10] Liao H, Shi J, Wen K, et al. Molecular targets of ferroptosis in hepatocellular carcinoma[J]. J Hepatocell Carcinoma, 2021, 8: 985-996.

[11] Yang Y, Wang Y, Guo L, et al. Interaction between macrophages and ferroptosis[J]. Cell Death Dis, 2022, 13(4): 355.

[12] Dixon SJ, Olzmann JA. The cell biology of ferroptosis[J]. Nat Rev Mol Cell Biol, 2024, 25(6): 424-442.

[13] Cheung JCT, Deng G, Wong N, et al. More than a duologue: In-depth insights into epitranscriptomics and ferroptosis[J]. Front Cell Dev Biol, 2022, 10: 982606.

[14] Liang D, Minikes AM, Jiang X. Ferroptosis at the intersection of lipid metabolism and cellular signaling. Mol Cell. 2022 Jun 16;82(12):2215-2227.

[15] Li X, Meng F, Wang H, et al. Iron accumulation and lipid peroxidation: implication of ferroptosis in hepatocellular carcinoma[J]. Front Endocrinol (Lausanne), 2024, 14: 1319969.

[16] Liu Y, Lu S, Wu LL, et al. The diversified role of mitochondria in ferroptosis in cancer[J]. Cell Death Dis, 2023, 14(8): 519.

[17] Zhong S, Wang Z, Yang J, et al. Ferroptosis-related oxaliplatin resistance in multiple cancers: Potential roles and therapeutic implications[J]. Heliyon, 2024, 10(18): e37613.

[18] Xu Y, Xing Z, Abdalla Ibrahim Suliman R, et al. Ferroptosis in liver cancer: a key role of post-translational modifications[J]. Front Immunol, 2024, 15: 1375589.

[19] Li Y, Zhu J, Yu Z, et al. Regulation of apoptosis by ubiquitination in liver cancer[J]. Am J Cancer Res, 2023, 13(10): 4832-4871.

[20] Zhang K, Zhang Q, Jia R, et al. A comprehensive review of the relationship between autophagy and sorafenib-resistance in hepatocellular carcinoma: ferroptosis is noteworthy[J]. Front Cell Dev Biol, 2023, 11: 1156383.

[21] Hao Y, Shao J, Lian N, et al. Metabolic cell death in cancer: mechanisms and therapeutic potential[J]. Apoptosis, 2025, 30(11-12): 2588-2611.

[22] Mao C, Wang M, Zhuang L, et al. Metabolic cell death in cancer: ferroptosis, cuproptosis, disulfidptosis, and beyond[J]. Protein Cell, 2024, 15(9): 642-660.

[23] Tong X, Tang R, Xiao M, et al. Targeting cell death pathways for cancer therapy: recent developments in necroptosis, pyroptosis, ferroptosis, and cuproptosis research[J]. J Hematol Oncol, 2022, 15(1): 174..

[24] Liu RJ, Yu XD, Yan SS, et al. Ferroptosis, pyroptosis and necroptosis in hepatocellular carcinoma immunotherapy: Mechanisms and immunologic landscape (Review)[J]. Int J Oncol, 2024, 64(6): 63.

[25] Li J, Bao H, Huang Z, et al. Little things with significant impact: miRNAs in hepatocellular carcinoma[J]. Front Oncol, 2023, 13: 1191070.

[26] Zhong J, Jiang R, Liu N, et al. Iron-immune crosstalk at the maternal-fetal interface: emerging mechanisms in the pathogenesis of preeclampsia[J]. Antioxidants (Basel), 2025, 14(7): 890.

[27] Zou K, Liu W, Xia W, et al. Ferroptosis in hypertriglyceridemic acute pancreatitis: Mechanisms and therapeutic implications[J]. J Inflamm Res, 2025, 18: 18115-18135.

[28] Cui K, Wang K, Huang Z. Ferroptosis and the tumor microenvironment[J]. J Exp Clin Cancer Res, 2024, 43(1): 315.

[29] Wang K, Wang J, Zhang J, et al. Ferroptosis in glioma immune microenvironment: opportunity and challenge[J]. Front Oncol, 2022, 12: 917634.

[30] Li S, Gao M, Li Z, et al. p53 and P-glycoprotein influence chemoresistance in hepatocellular carcinoma[J]. Front Biosci (Elite Ed), 2018, 10(3): 461-468.

[31] Chen F, Kang R, Tang D, et al. Ferroptosis: principles and significance in health and disease[J]. J Hematol Oncol, 2024, 17(1): 41.

[32] Zhao P, Yin S, Qiu Y, et al. Ferroptosis and pyroptosis are connected through autophagy: a new perspective of overcoming drug resistance[J]. Mol Cancer, 2025, 24(1): 23.

[33] Li L, Wang X, Xu H, et al. Perspectives and mechanisms for targeting ferroptosis in the treatment of hepatocellular carcinoma[J]. Front Mol Biosci, 2022, 9: 947208.

[34] Huang Z, Xia H, Cui Y, Yam JWP, Xu Y. Ferroptosis: From Basic Research to Clinical Therapeutics in Hepatocellular Carcinoma. J Clin Transl Hepatol. 2023 Feb 28;11(1):207-218.

[35] Bekric D, Ocker M, Mayr C, Stintzing S, Ritter M, Kiesslich T, Neureiter D. Ferroptosis in Hepatocellular Carcinoma: Mechanisms, Drug Targets and Approaches to Clinical Translation. Cancers (Basel). 2022 Apr 4;14(7):1826.

[36] Han JF, Jia ZY, Fan X, et al. Mechanisms of ferroptosis in primary hepatocellular carcinoma and progress of artificial intelligence-based predictive modeling in hepatocellular carcinoma[J]. World J Gastroenterol, 2025, 31(41): 111174.

[37] Guo L, Hu C, Yao M, et al. Mechanism of sorafenib resistance associated with ferroptosis in HCC[J]. Front Pharmacol, 2023, 14: 1207496.

[38] Chen R, Hu X, Huang Y, et al. Regulated cell death in lenvatinib resistance of hepatocellular carcinoma: from molecular mechanisms to therapeutic strategies[J]. Int J Biol Sci, 2025, 21(5): 2012-2026.

[39] Li C, Zhao W, Geng D, et al. Targeting the interplay of cGAS-STING and ferroptosis by nanomedicine in the treatment of cancer[J]. J Exp Clin Cancer Res, 2025, 44(1): 249.

[40] Liu B, Liu L, Liu Y. Targeting cell death mechanisms: the potential of autophagy and ferroptosis in hepatocellular carcinoma therapy[J]. Front Immunol, 2024, 15: 1450487.