Skip to main content

Advertisement

Log in

Research progress on the occurrence and therapeutic mechanism of ferroptosis in NSCLC

  • Review
  • Published:
Naunyn-Schmiedeberg's Archives of Pharmacology Aims and scope Submit manuscript

Abstract

Ferroptosis refers to a novel way of cell death, inconsistent with the conventional concept of apoptosis and necrosis. It shows a close association with iron metabolism and oxidative damage, as marked by the significant increase of reactive oxygen species, the decreases of mitochondrial volume, and the thickening of membrane density. Recent studies confirmed that ferroptosis is closely associated with the occurrence, development, and therapy of the tumors. As impacted by the high levels of reactive oxygen species and lipid peroxides in lung cancer tissues, it is suggested that ferroptosis is more likely to occur in lung cancer tissues, which may act as a novel approach for non-small cell lung cancer (NSCLC) therapy. In the present study, the research achievements in recent years on the regulating mechanism of ferroptosis and its effect on the occurrence and the therapy of lung cancer are reviewed.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

Abbreviations

NSCLC :

non-small cell lung cancer

ROS :

reactive oxygen species

L-OOH :

lipid hydroperoxides

ACSL4 :

acyl-CoA synthetase long-chain family member 4

PUFAs :

polyunsaturated fatty acids

FSP1 :

ferroptosis suppressing protein 1

AIFM2 :

apoptosis inducing factor mitochondria 2

GSH :

glutathione

GPX 4 :

glutathione peroxidase 4

SOCS1 :

suppressor of cytokine signaling 1

EGFR :

epidermal growth factor receptor

TF :

transferrin

TFR1 :

transferrin receptor 1

FTH :

ferritin heavy chain

STEAP3 :

six-transmembrane epithelial antigen of prostate 3

FTL :

ferritin light chain

DMT1 :

divalent metal transporter 1

HSPB1 :

heat shock protein B1

IREB2 :

iron response element-binding protein 2

NCOA4 :

nuclear receptor coactivator 4 protein

HO-1 :

heme oxygenase-1

ISCU :

iron–sulfur cluster assembly enzyme

DHAN :

dihydroartemisinin

LPCAT3 :

lysophosphatidylcholine acyltransferase 3

PEBP1 :

phosphatidylethanolamine binding protein 1

SFA :

saturated fatty acid

VDACs :

voltage-dependent anion channel

lncRNAs :

long non-coding RNA

G3BP1 :

Ras-GTPase activated protein binding to protein 1

STAT3 :

signal transducer and activator of transcription 3

NFS-1 :

cysteine desulfurase

SCLC :

small cell lung cancer

IO NPs :

iron oxide nanoparticles

CTLA4 :

cytotoxic T-lymphocyte-associated protein 4

IKE :

imidazole ketone erastin

DLBCL :

diffuse large B cell lymphoma

TKI :

tyrosine kinase inhibitor

IR :

ionizing radiation

References

  • Alvarez SW, Sviderskiy VO, Terzi EM et al (2017) NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature 551(7682):639–643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anderson GJ (2017) Frazer DM Current understanding of iron homeostasis. Am J Clin Nutr 106(Suppl 6):1559S–1566S

    Article  PubMed  PubMed Central  Google Scholar 

  • Bersuker K, Hendricks JM, Li Z et al (2019) The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575(7784):688–692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chang L-C, Chiang S-K, Chen S-E et al (2018) Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis. Cancer Lett 416124-137

  • Chen L, Li X, Liu L et al (2015) Erastin sensitizes glioblastoma cells to temozolomide by restraining xCT and cystathionine-γ-lyase function. Oncol Rep 33(3):1465–1474

    Article  CAS  PubMed  Google Scholar 

  • Chen P, Wu Q, Feng J et al (2020) Erianin, a novel dibenzyl compound in Dendrobium extract, inhibits lung cancer cell growth and migration via calcium/calmodulin-dependent ferroptosis. Signal Transduct Target Ther 5(1):51

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cox AD, Fesik SW, Kimmelman AC et al (2014) Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov 13(11):828–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cui W, Liu D, Gu W et al (2021) Peroxisome-driven ether-linked phospholipids biosynthesis is essential for ferroptosis. Cell Death Differ 28(8):2536–2551

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dixon SJ, Lemberg KM, Lamprecht MR et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 149(5):1060–1072

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dixon SJ, Patel DN, Welsch M et al (2014) Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife 3e02523

  • Dixon SJ, Winter GE, Musavi LS et al (2015) Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem Biol 10(7):1604–1609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doll S, Proneth B, Tyurina YY et al (2017) ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol 13(1):91–98

    Article  CAS  PubMed  Google Scholar 

  • Doll S, Freitas FP, Shah R et al (2019) FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575(7784):693–698

    Article  CAS  PubMed  Google Scholar 

  • Dolma S, Lessnick SL, Hahn WC et al (2003) Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells. Cancer Cell 3(3):285–296

    Article  CAS  PubMed  Google Scholar 

  • Du J, Wang T, Li Y et al (2019) DHA inhibits proliferation and induces ferroptosis of leukemia cells through autophagy dependent degradation of ferritin. Free Radic Biol Med 131356-369

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Feng J, Jiang W, Liu Y et al (2020) Blocking STAT3 by pyrvinium pamoate causes metabolic lethality in KRAS-mutant lung cancer. Biochem Pharmacol 177113960

  • Friedmann Angeli JP, Schneider M, Proneth B et al (2014) Inactivation of the ferroptosis regulator Gpx4 triggers acute renal failure in mice. Nat Cell Biol 16(12):1180–1191

    Article  CAS  PubMed  Google Scholar 

  • Gammella E, Recalcati S, Rybinska I et al (2015) Iron-induced damage in cardiomyopathy: oxidative-dependent and independent mechanisms. Oxidative Med Cell Longev 2015230182

  • Gao M, Monian P (2015) Jiang X Metabolism and iron signaling in ferroptotic cell death. Oncotarget 6(34):35145–35146

    Article  PubMed  PubMed Central  Google Scholar 

  • Gao M, Monian P, Quadri N et al (2015) Glutaminolysis and transferrin regulate ferroptosis. Mol Cell 59(2):298–308

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gaschler MM, Andia AA, Liu H et al (2018) FINO initiates ferroptosis through GPX4 inactivation and iron oxidation. Nat Chem Biol 14(5):507–515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo J, Xu B, Han Q et al (2018) Ferroptosis: a novel anti-tumor action for cisplatin. Cancer Res Treat 50(2):445–460

    Article  CAS  PubMed  Google Scholar 

  • Hangauer MJ, Viswanathan VS, Ryan MJ et al (2017) Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature 551(7679):247–250

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hassannia B, Wiernicki B, Ingold I et al (2018) Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. J Clin Invest 128(8):3341–3355

    Article  PubMed  PubMed Central  Google Scholar 

  • Hou W, Xie Y, Song X et al (2016) Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12(8):1425–1428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ji X, Qian J, Rahman SMJ et al (2018) xCT (SLC7A11)-mediated metabolic reprogramming promotes non-small cell lung cancer progression. Oncogene. 37(36):5007–5019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang L, Kon N, Li T et al (2015) Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 520(7545):57–62

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang M, Qiao M, Zhao C et al (2020) Targeting ferroptosis for cancer therapy: exploring novel strategies from its mechanisms and role in cancers. Transl Lung Cancer Res 9(4):1569–1584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kagan VE, Mao G, Qu F et al (2017) Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol 13(1):81–90

    Article  CAS  PubMed  Google Scholar 

  • Kang R (2017) Tang D Autophagy and ferroptosis - what’s the connection? Curr Pathobiol Rep 5(2):153–159

    Article  PubMed  PubMed Central  Google Scholar 

  • Kazan HH, Urfali-Mamatoglu C (2017) Gunduz U Iron metabolism and drug resistance in cancer. Biometals. 30(5):629–641

    Article  CAS  PubMed  Google Scholar 

  • Kuang Y (2019) Wang Q Iron and lung cancer. Cancer Lett 46456-61

  • Lachaier E, Louandre C, Godin C et al (2014) Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res 34(11):6417–6422

    CAS  PubMed  Google Scholar 

  • Lee H, Jeong AJ (2019) Ye S-K Highlighted STAT3 as a potential drug target for cancer therapy. BMB Rep 52(7):415–423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Cao F, Yin H-L et al (2020) Ferroptosis: past, present and future. Cell Death Dis 11(2):88

    Article  PubMed  PubMed Central  Google Scholar 

  • Lin C-H, Lin P-P, Lin C-Y et al (2016) Decreased mRNA expression for the two subunits of system xc(-), SLC3A2 and SLC7A11, in WBC in patients with schizophrenia: evidence in support of the hypo-glutamatergic hypothesis of schizophrenia. J Psychiatr Res 7258-63

  • Liu T, Liu W, Zhang M et al (2018) Ferrous-supply-regeneration nanoengineering for cancer-cell-specific ferroptosis in combination with imaging-guided photodynamic therapy. ACS Nano 12(12):12181–12192

    Article  CAS  PubMed  Google Scholar 

  • Lou J-S, Zhao L-P, Huang Z-H et al (2021) Ginkgetin derived from Ginkgo biloba leaves enhances the therapeutic effect of cisplatin via ferroptosis-mediated disruption of the Nrf2/HO-1 axis in EGFR wild-type non-small-cell lung cancer. Phytomedicine 80153370

  • Louandre C, Ezzoukhry Z, Godin C et al (2013) Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int J Cancer 133(7):1732–1742

    Article  CAS  PubMed  Google Scholar 

  • Louandre C, Marcq I, Bouhlal H et al (2015) The retinoblastoma (Rb) protein regulates ferroptosis induced by sorafenib in human hepatocellular carcinoma cells. Cancer Lett 356(2 Pt B):971–977

    Article  CAS  PubMed  Google Scholar 

  • Manz DH, Blanchette NL, Paul BT et al (2016) Iron and cancer: recent insights. Ann N Y Acad Sci 1368(1):149–161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mao C, Wang X, Liu Y et al (2018) A G3BP1-interacting lncRNA promotes ferroptosis and apoptosis in cancer via nuclear sequestration of p53. Cancer Res 78(13):3484–3496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • McBean GJ The transsulfuration pathway: a source of cysteine for glutathione in astrocytes. Amino Acids42(1),199-205 (2012).

  • Mohrherr J, Uras IZ, Moll HP et al (2020) STAT3: versatile functions in non-small cell lung cancer. Cancers (Basel) 12(5)

  • Nyiramana MM, Cho SB, Kim E-J et al (2020) Sea hare hydrolysate-induced reduction of human non-small cell lung cancer cell growth through regulation of macrophage polarization and non-apoptotic regulated cell death pathways. Cancers (Basel) 12(3)

  • Orcutt KP, Parsons AD, Sibenaller ZA et al (2011) Erlotinib-mediated inhibition of EGFR signaling induces metabolic oxidative stress through NOX4. Cancer Res 71(11):3932–3940

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pa M, Xiao H, Yu C et al (2017) Enhanced cisplatin chemotherapy by iron oxide nanocarrier-mediated generation of highly toxic reactive oxygen species. Nano Lett 17(2):928–937

    Article  Google Scholar 

  • Poursaitidis I, Wang X, Crighton T et al (2017) Oncogene-selective sensitivity to synchronous cell death following modulation of the amino acid nutrient cystine. Cell Rep 18(11):2547–2556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roh J-L, Kim EH, Jang H et al (2017) Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol 11254-262

  • Román M, Baraibar I, López I et al (2018) KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target. Mol Cancer 17(1):33

    Article  PubMed  PubMed Central  Google Scholar 

  • Saint-Germain E, Mignacca L, Vernier M et al (2017) SOCS1 regulates senescence and ferroptosis by modulating the expression of p53 target genes. Aging (Albany NY) 9(10):2137–2162

    Article  CAS  Google Scholar 

  • Schoenfeld JD, Sibenaller ZA, Mapuskar KA et al (2017) O and HO-mediated disruption of Fe metabolism causes the differential susceptibility of NSCLC and GBM cancer cells to pharmacological ascorbate. Cancer Cell 31(4)

  • Shen Z, Song J, Yung BC et al (2018) Emerging strategies of cancer therapy based on ferroptosis. Adv Mater 30(12):e1704007

    Article  PubMed  PubMed Central  Google Scholar 

  • Shimada K, Hayano M, Pagano NC et al (2016a) Cell-Line selectivity improves the predictive power of pharmacogenomic analyses and helps identify NADPH as biomarker for ferroptosis sensitivity. Cell Chem Biol 23(2):225–235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shimada K, Skouta R, Kaplan A et al (2016b) Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol 12(7):497–503

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sun X, Ou Z, Chen R et al (2016) Activation of the p62-Keap1-NRF2 pathway protects against ferroptosis in hepatocellular carcinoma cells. Hepatology 63(1):173–184

    Article  CAS  PubMed  Google Scholar 

  • Vanden Berghe T, Linkermann A, Jouan-Lanhouet S et al (2014) Regulated necrosis: the expanding network of non-apoptotic cell death pathways. Nat Rev Mol Cell Biol 15(2):135–147

    Article  Google Scholar 

  • Viswanathan VS, Ryan MJ, Dhruv HD et al (2017) Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547(7664):453–457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang B, Zhang J, Song F et al (2016) EGFR regulates iron homeostasis to promote cancer growth through redistribution of transferrin receptor 1. Cancer Lett 381(2):331–340

    Article  CAS  PubMed  Google Scholar 

  • Wang M, Mao C, Ouyang L et al (2019a) Long noncoding RNA LINC00336 inhibits ferroptosis in lung cancer by functioning as a competing endogenous RNA. Cell Death Differ 26(11):2329–2343

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wang W, Green M, Choi JE et al (2019b) CD8 T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569(7755):270–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wenzel SE, Tyurina YY, Zhao J et al (2017) PEBP1 wardens ferroptosis by enabling lipoxygenase generation of lipid death signals. Cell 171(3)

  • Werner ER, Keller MA, Sailer S et al (2020) The gene encodes plasmanylethanolamine desaturase which introduces the characteristic vinyl ether double bond into plasmalogens. Proc Natl Acad Sci U S A 117(14):7792–7798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yagoda N, von Rechenberg M, Zaganjor E et al (2007) RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 447(7146):864–868

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang WS, SriRamaratnam R, Welsch ME et al (2014) Regulation of ferroptotic cancer cell death by GPX4. Cell 156(1-2):317–331

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang WS, Kim KJ, Gaschler MM et al (2016) Peroxidation of polyunsaturated fatty acids by lipoxygenases drives ferroptosis. Proc Natl Acad Sci U S A 113(34):E4966–E4975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang W-H, Ding C-KC, Sun T et al (2019) The hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma. Cell Rep 28(10)

  • Yu H, Han Z, Xu Z et al (2019) RNA sequencing uncovers the key long non-coding RNAs and potential molecular mechanism contributing to XAV939-mediated inhibition of non-small cell lung cancer. Oncol Lett 17(6):4994–5004

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yuan H, Li X, Zhang X et al (2016) Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun 478(3):1338–1343

    Article  CAS  PubMed  Google Scholar 

  • Zhang Y, Tan H, Daniels JD et al (2019a) Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell. Chem Biol 26(5)

  • Zhang D, Cui P, Dai Z et al (2019b) Tumor microenvironment responsive FePt/MoS nanocomposites with chemotherapy and photothermal therapy for enhancing cancer immunotherapy. Nanoscale 11(42):19912–19922

    Article  CAS  PubMed  Google Scholar 

  • Zheng D-W, Lei Q, Zhu J-Y et al (2017) Switching apoptosis to ferroptosis: metal-organic network for high-efficiency anticancer therapy. Nano Lett 17(1):284–291

    Article  CAS  PubMed  Google Scholar 

  • Zhou Z, Song J, Tian R et al (2017) Activatable singlet oxygen generation from lipid hydroperoxide nanoparticles for cancer therapy. Angew Chem Int Ed Eng 56(23):6492–6496

    Article  CAS  Google Scholar 

  • Zou Y, Henry WS, Ricq EL et al (2020) Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature 585(7826):603–608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Availability of data and materials

Not applicable.

Author information

Authors and Affiliations

Authors

Contributions

LM Z and YF Z conceived and designed the research. YF Z, RX G, and J L found some paper, YF Z wrote the paper, and LM Z revised the manuscript. All authors approved of the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Liangming Zhu.

Ethics declarations

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The 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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Y., Guo, R., Li, J. et al. Research progress on the occurrence and therapeutic mechanism of ferroptosis in NSCLC. Naunyn-Schmiedeberg's Arch Pharmacol 395, 1–12 (2022). https://doi.org/10.1007/s00210-021-02178-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00210-021-02178-z

Keywords

Navigation