Ferroptosis and Tumor Drug Resistance: Current Status and Major Challenges

Overview

Journal Front Pharmacol

Date 2022 Jun 7

PMID 35668934

Authors

Zhenyu Nie

Mei Chen

Yuanhui Gao

Denggao Huang

Hui Cao

Yanling Peng

Na Guo

Fei Wang

Shufang Zhang

Affiliations

Soon will be listed here.

Abstract

Ferroptosis is a novel type of regulated cell death, whose unique metabolic characteristics are commonly used to evaluate the conditions of various diseases especially in tumors. Accumulating evidence supports that ferroptosis can regulate tumor development, metastasis, and therapeutic responses. Considering to the important role of chemotherapy in tumor treatment, drug resistance has become the most serious challenge. Revealing the molecular mechanism of ferroptosis is expected to solve tumor drug resistance and find new therapies to treat cancers. In this review, we discuss the relationship between ferroptosis and tumor drug resistance, summarize the abnormal ferroptosis in tissues of different cancer types and current research progress and challenges in overcoming treatment resistance, and explore the concept of targeting ferroptosis to improve tumor treatment outcomes.

Citing Articles

STAT1 increases the sensitivity of lung adenocarcinoma to carbon ion irradiation via HO-1-mediated ferroptosis.

Chen Y, Wang D, Luo H, Tan M, Wang Q, Wu X Mol Cell Biochem. 2025; .

PMID: 40087208 DOI: 10.1007/s11010-025-05240-z.

SREBF1-based metabolic reprogramming in prostate cancer promotes tumor ferroptosis resistance.

Wei G, Huang Y, Li W, Xie Y, Zhang D, Niu Y Cell Death Discov. 2025; 11(1):75.

PMID: 39988626 PMC: 11847930. DOI: 10.1038/s41420-025-02354-7.

New Insights into Aspirin's Anticancer Activity: The Predominant Role of Its Iron-Chelating Antioxidant Metabolites.

Kontoghiorghes G Antioxidants (Basel). 2025; 14(1).

PMID: 39857363 PMC: 11763074. DOI: 10.3390/antiox14010029.

Targeting regulated cell death pathways in cancers for effective treatment: a comprehensive review.

Saxena R, Welsh C, He Y Front Cell Dev Biol. 2024; 12:1462339.

PMID: 39620145 PMC: 11604647. DOI: 10.3389/fcell.2024.1462339.

Improving understanding of ferroptosis: Molecular mechanisms, connection with cellular senescence and implications for aging.

De Leon-Oliva D, Boaru D, Minaya-Bravo A, De Castro-Martinez P, Fraile-Martinez O, Garcia-Montero C Heliyon. 2024; 10(21):e39684.

PMID: 39553553 PMC: 11564042. DOI: 10.1016/j.heliyon.2024.e39684.

References

Jang J, Kim M, Jeon Y, Joung Y, Park K, Kim C . Adenovirus adenine nucleotide translocator-2 shRNA effectively induces apoptosis and enhances chemosensitivity by the down-regulation of ABCG2 in breast cancer stem-like cells. Exp Mol Med. 2011; 44(4):251-9. PMC: 3349907. DOI: 10.3858/emm.2012.44.4.019. View

Meng E, Mitra A, Tripathi K, Finan M, Scalici J, McClellan S . ALDH1A1 maintains ovarian cancer stem cell-like properties by altered regulation of cell cycle checkpoint and DNA repair network signaling. PLoS One. 2014; 9(9):e107142. PMC: 4162571. DOI: 10.1371/journal.pone.0107142. View

Maines M . Heme oxygenase: function, multiplicity, regulatory mechanisms, and clinical applications. FASEB J. 1988; 2(10):2557-68. View

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(12):3830-3852. PMC: 5521825. DOI: 10.1039/c6cs00592f. View

Wang J, Huang S, Marzese D, Hsu S, Kawas N, Chong K . Epigenetic changes of EGFR have an important role in BRAF inhibitor-resistant cutaneous melanomas. J Invest Dermatol. 2014; 135(2):532-541. PMC: 4307785. DOI: 10.1038/jid.2014.418. View

Teshima K, Nara M, Watanabe A, Ito M, Ikeda S, Hatano Y . Dysregulation of BMI1 and microRNA-16 collaborate to enhance an anti-apoptotic potential in the side population of refractory mantle cell lymphoma. Oncogene. 2013; 33(17):2191-203. DOI: 10.1038/onc.2013.177. View

Liu M, Ge Y, Payton S, Aboukameel A, Buck S, Flatley R . Transcriptional regulation of the human reduced folate carrier in childhood acute lymphoblastic leukemia cells. Clin Cancer Res. 2006; 12(2):608-16. DOI: 10.1158/1078-0432.CCR-05-1954. View

Yun C, Mengwasser K, Toms A, Woo M, Greulich H, Wong K . The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP. Proc Natl Acad Sci U S A. 2008; 105(6):2070-5. PMC: 2538882. DOI: 10.1073/pnas.0709662105. View

Shin D, Kim E, Lee J, Roh J . Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic Biol Med. 2018; 129:454-462. DOI: 10.1016/j.freeradbiomed.2018.10.426. View

10.

Harada N, Kanayama M, Maruyama A, Yoshida A, Tazumi K, Hosoya T . Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages. Arch Biochem Biophys. 2011; 508(1):101-9. DOI: 10.1016/j.abb.2011.02.001. View

11.

Sun X, Ou Z, Xie M, Kang R, Fan Y, Niu X . HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene. 2015; 34(45):5617-25. PMC: 4640181. DOI: 10.1038/onc.2015.32. View

12.

Huang C, Yang M, Deng J, Li P, Su W, Jiang R . Upregulation and activation of p53 by erastin‑induced reactive oxygen species contribute to cytotoxic and cytostatic effects in A549 lung cancer cells. Oncol Rep. 2018; 40(4):2363-2370. DOI: 10.3892/or.2018.6585. View

13.

Gilbert L, Hemann M . DNA damage-mediated induction of a chemoresistant niche. Cell. 2010; 143(3):355-66. PMC: 2972353. DOI: 10.1016/j.cell.2010.09.043. View

14.

Gorre M, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao P . Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001; 293(5531):876-80. DOI: 10.1126/science.1062538. View

15.

Shi Z, Fan Z, Chen Y, Xie X, Jiang W, Wang W . Ferroptosis in Carcinoma: Regulatory Mechanisms and New Method for Cancer Therapy. Onco Targets Ther. 2020; 12:11291-11304. PMC: 6927606. DOI: 10.2147/OTT.S232852. View

16.

Kobayashi I, Takahashi F, Nurwidya F, Nara T, Hashimoto M, Murakami A . Oct4 plays a crucial role in the maintenance of gefitinib-resistant lung cancer stem cells. Biochem Biophys Res Commun. 2016; 473(1):125-132. DOI: 10.1016/j.bbrc.2016.03.064. View

17.

Conrad M, Friedmann Angeli J, Vandenabeele P, Stockwell B . Regulated necrosis: disease relevance and therapeutic opportunities. Nat Rev Drug Discov. 2016; 15(5):348-66. PMC: 6531857. DOI: 10.1038/nrd.2015.6. View

18.

Sun X, Ou Z, Chen R, Niu X, Chen D, Kang R . Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology. 2015; 63(1):173-84. PMC: 4688087. DOI: 10.1002/hep.28251. View

19.

Rouault T . The intestinal heme transporter revealed. Cell. 2005; 122(5):649-51. DOI: 10.1016/j.cell.2005.08.027. View

20.

Yu Y, Xie Y, Cao L, Yang L, Yang M, Lotze M . The ferroptosis inducer erastin enhances sensitivity of acute myeloid leukemia cells to chemotherapeutic agents. Mol Cell Oncol. 2016; 2(4):e1054549. PMC: 4905356. DOI: 10.1080/23723556.2015.1054549. View