Ferroptosis Unleashed: A Bold Approach to Revolutionize Cancer Treatment

Authors

  • Shrabani Manna Department of Pharmacy University of technology Vatika, Jaipur, Rajasthan
  • Ayushi Patel SMT R. D. Gardi B Pharmacy College, Nyara, Rajkot, Gujarat
  • Dr. Gajendra Singh Tyagi Department of Pharmacy University of technology Vatika, Jaipur, Rajasthan

DOI:

https://doi.org/10.22270/ajprd.v13i4.1597

Abstract

One of the deadliest diseases that affects world health is cancer. More than one cell death pathwayhas been found, one of which is ferroptosis. In 2012, the word ferroptosis was introduced to characterize a regulated cell death dependent on iron and arising from the build-up of reactive oxygen species derived from lipids. This particular form of cell death was discovered to possess unique molecular traits that set it apart from other types of regulated cell death. Ferroptosis characteristics have been noted. These chemical characteristics have appeared on occasion during the past few decades, but it wasn't until recently that they were identified as proof of a unique type of cell death. Here, we outline the development that led to the emergence of the idea of ferroptosis, as well as the history of data consistent with its current description. We also review the latest applications and implications of ferroptotic death pathway modifications.

 

Downloads

Download data is not yet available.

Author Biographies

Shrabani Manna, Department of Pharmacy University of technology Vatika, Jaipur, Rajasthan

Department of Pharmacy University of technology Vatika, Jaipur, Rajasthan

Ayushi Patel, SMT R. D. Gardi B Pharmacy College, Nyara, Rajkot, Gujarat

SMT R. D. Gardi B Pharmacy College, Nyara, Rajkot, Gujarat

Dr. Gajendra Singh Tyagi, Department of Pharmacy University of technology Vatika, Jaipur, Rajasthan

Department of Pharmacy University of technology Vatika, Jaipur, Rajasthan

References

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. Vol. 25, Cell Death and Differentiation. Nature Publishing Group; 2018. p. 486–541.

Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. PubMed. 2014 Jan 16;156(1–2):317–31.

Chen Z, Wang W, Abdul Razak SR, Han T, Ahmad NH, Li X. Ferroptosis as a potential target for cancer therapy. Vol. 14, Cell Death and Disease. Springer Nature; 2023.

Doll S, Conrad M. Iron and ferroptosis: A still ill-defined liaison. Vol. 69, IUBMB Life. Blackwell Publishing Ltd; 2017. p. 423–34.

Conrad M, Angeli JPF, Vandenabeele P, Stockwell BR. Regulated necrosis: Disease relevance and therapeutic opportunities. Vol. 15, Nature Reviews Drug Discovery. Nature Publishing Group; 2016. p. 348–66.

Li J, Cao F, Yin H liang, Huang Z jian, Lin Z tao, Mao N, et al. Ferroptosis: past, present, and future. Vol. 11, Cell Death and Disease. Springer Nature; 2020.

Kist M, Vucic D. Cell death pathways: intricate connections and disease implications. EMBO J. 2021 Mar;40(5).

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. Vol. 25, Cell Death and Differentiation. Nature Publishing Group; 2018. p. 486–541.

Fuchs Y, Steller H. Programmed cell death in animal development and disease. Vol. 147, Cell. Elsevier B.V.; 2011. p. 742–58.

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 May 25;149(5):1060–72.

Weinlich R, Oberst A, Beere HM, Green DR. Necroptosis in development, inflammation and disease. Vol. 18, Nature Reviews Molecular Cell Biology. Nature Publishing Group; 2017. p. 127–36.

Liu J, Kuang F, Kang R, Tang D. Alkaliptosis: a new weapon for cancer therapy. Vol. 27, Cancer Gene Therapy. Springer Nature; 2020. p. 267–9.

Song X, Zhu S, Xie Y, Liu J, Sun L, Zeng D, et al. JTC801 Induces pH-dependent Death Specifically in Cancer Cells and Slows Growth of Tumors in Mice. Gastroenterology. 2018 Apr 1;154(5):1480–93.

Yan D, Wu Z, Qi X. Ferroptosis-related metabolic mechanism and nanoparticulate anticancer drug delivery systems based on ferroptosis. Vol. 31, Saudi Pharmaceutical Journal. Elsevier B.V.; 2023. p. 554–68.

Bergsbaken T, Fink SL, Cookson BT. Pyroptosis: Host cell death and inflammation. Vol. 7, Nature Reviews Microbiology. 2009. p. 99–109.

Christofferson DE, Yuan J. Necroptosis as an alternative form of programmed cell death. Vol. 22, Current Opinion in Cell Biology. 2010. p. 263–8.

Dolma S, Lessnick SL, Hahn WC, Stockwell BR. Identification of genotype-selective antitumor agents using synthetic lethal chemical screening in engineered human tumor cells.

Yagoda N, Von Rechenberg M, Zaganjor E, Bauer AJ, Yang WS, Fridman DJ, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007 Jun 14;447(7146):864–8.

Yang WS, Stockwell BR. Synthetic Lethal Screening Identifies Compounds Activating Iron-Dependent, Nonapoptotic Cell Death in Oncogenic-RAS-Harboring Cancer Cells. Chem Biol. 2008 Mar 21;15(3):234–45.

Green DR, Levine B. To be or not to be? How selective autophagy and cell death govern cell fate. Vol. 157, Cell. Elsevier B.V.; 2014. p. 65–75.

Green DR, Victor B. The pantheon of the fallen: Why are there so many forms of cell death? Vol. 22, Trends in Cell Biology. 2012. p. 555–6.

Oltvai ZN, Milkman CL, Korsmeyer SJ. Bcl-2 Heterodimerizes In Vivo with a Conserved Homolog, Bax, That Accelerates Programmed Cell Death. Vol. 74, Cell. 1993.

Sun L, Wang H, Wang Z, He S, Chen S, Liao D, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012 Jan 20;148(1–2):213–27.

Kayagaki N, Stowe IB, Lee BL, O’Rourke K, Anderson K, Warming S, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015 Oct 29;526(7575):666–71.

Shi J, Zhao Y, Wang K, Shi X, Wang Y, Huang H, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015 Oct 29;526(7575):660–5.

Hirschhorn T, Stockwell BR. The development of the concept of ferroptosis. Vol. 133, Free Radical Biology and Medicine. Elsevier Inc.; 2019. p. 130–43.

Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Vol. 144, Cell. 2011. p. 646–74.

Carneiro BA, El-Deiry WS. Targeting apoptosis in cancer therapy. Vol. 17, Nature Reviews Clinical Oncology. Nature Research; 2020. p. 395–417.

Xie Y, Hou W, Song X, Yu Y, Huang J, Sun X, et al. Ferroptosis: Process and function. Vol. 23, Cell Death and Differentiation. Nature Publishing Group; 2016. p. 369–79.

Liu Y, Levine B. Autosis and autophagic cell death: The dark side of autophagy. Vol. 22, Cell Death and Differentiation. Nature Publishing Group; 2015. p. 367–76.

Kumari R, Jat P. Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence-Associated Secretory Phenotype. Vol. 9, Frontiers in Cell and Developmental Biology. Frontiers Media S.A.; 2021.

Ge Y, Huang M, Yao YM. Efferocytosis and Its Role in Inflammatory Disorders. Vol. 10, Frontiers in Cell and Developmental Biology. Frontiers Media S.A.; 2022.

Morioka S, Maueröder C, Ravichandran KS. Living on the Edge: Efferocytosis at the Interface of Homeostasis and Pathology. Vol. 50, Immunity. Cell Press; 2019. p. 1149–62.

Kianfar M, Balcerak A, Chmielarczyk M, Tarnowski L, Grzybowska EA. Cell Death by Entosis: Triggers, Molecular Mechanisms and Clinical Significance. Vol. 23, International Journal of Molecular Sciences. MDPI; 2022.

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 May 25;149(5):1060–72.

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 Jul 17;10(7):1604–9.

Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019 Nov 28;575(7784):693–8.

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 May 25;149(5):1060–72.

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(1–2):317–31.

Alvarez SW, Sviderskiy VO, Terzi EM, Papagiannakopoulos T, Moreira AL, Adams S, et al. NFS1 undergoes positive selection in lung tumours and protects cells from ferroptosis. Nature. 2017 Nov 30;551(7682):639–43.

Ubellacker JM, Tasdogan A, Ramesh V, Shen B, Mitchell EC, Martin-Sandoval MS, et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature. 2020 Sep 3;585(7823):113–8.

Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017 Jul 27;547(7664):453–7.

Andrews NC, Schmidt PJ. Iron homeostasis. Vol. 69, Annual Review of Physiology. 2007. p. 69–85.

Gao M, Monian P, Pan Q, Zhang W, Xiang J, Jiang X. Ferroptosis is an autophagic cell death process. Cell Res. 2016 Sep 1;26(9):1021–32.

Hou W, Xie Y, Song X, Sun X, Lotze MT, Zeh HJ, et al. Autophagy promotes ferroptosis by degradation of ferritin. Vol. 12, Autophagy. Taylor and Francis Inc.; 2016. p. 1425–8.

Lieu PT, Heiskala M, Peterson PA, Yang Y. The roles of iron in health and disease [Internet]. Vol. 22, Molecular Aspects of Medicine. 2001. Available from: www.elsevier.com/locate/mam

Winterbourn CC. Toxicology Letters Toxicity of iron and hydrogen peroxide: the Fenton reaction.

Douda DN, Khan MA, Grasemann H, Palaniyar N. SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx. Proc Natl Acad Sci U S A. 2015 Mar 3;112(9):2817–22.

Park E, Chung SW. ROS-mediated autophagy increases intracellular iron levels and ferroptosis by ferritin and transferrin receptor regulation. Cell Death Dis. 2019 Nov 1;10(11).

Ding H, Chen S, Pan X, Dai X, Pan G, Li Z, et al. Transferrin receptor 1 ablation in satellite cells impedes skeletal muscle regeneration through activation of ferroptosis. J Cachexia Sarcopenia Muscle. 2021 Jun 1;12(3):746–68.

Wang Y, Yu L, Ding J, Chen Y. Iron metabolism in cancer. Vol. 20, International Journal of Molecular Sciences. MDPI AG; 2019.

Zhang C, Liu X, Jin S, Chen Y, Guo R. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Vol. 21, Molecular Cancer. BioMed Central Ltd; 2022.

Li J, Cao F, Yin H liang, Huang Z jian, Lin Z tao, Mao N, et al. Ferroptosis: past, present, and future. Vol. 11, Cell Death and Disease. Springer Nature; 2020.

Magtanong L, Ko PJ, Dixon SJ. Emerging roles for lipids in non-apoptotic cell death. Vol. 23, Cell Death and Differentiation. Nature Publishing Group; 2016. p. 1099–109.

Torii S, Shintoku R, Kubota C, Yaegashi M, Torii R, Sasaki M, et al. An essential role for functional lysosomes in ferroptosis of cancer cells. Biochemical Journal. 2016 Mar 15;473(6):769–77.

Santana-Codina N, Mancias JD. The role of NCOA4-mediated ferritinophagy in health and disease. Vol. 11, Pharmaceuticals. MDPI AG; 2018.

Battaglia AM, Chirillo R, Aversa I, Sacco A, Costanzo F, Biamonte F. Ferroptosis and cancer: Mitochondria meet the “iron maiden” cell death. Vol. 9, Cells. MDPI; 2020. p. 1–26.

Shen Y, Li X, Dong D, Zhang B, Xue Y, Shang P. Transferrin receptor 1 in cancer: a new sight for cancer therapy [Internet]. Vol. 8, Am J Cancer Res. 2018. Available from: www.ajcr.us/

Sun X, Ou Z, Xie M, Kang R, Fan Y, Niu X, et al. HSPB1 as a novel regulator of ferroptotic cancer cell death. Oncogene. 2015 Mar 2;34(45):5617–25.

Manz DH, Blanchette NL, Paul BT, Torti FM, Torti SV. Iron and cancer: Recent insights. Ann N Y Acad Sci. 2016 Mar 1;1368(1):149–61.

Imoto S, Kono M, Suzuki T, Shibuya Y, Sawamura T, Mizokoshi Y, et al. Haemin-induced cell death in human monocytic cells is consistent with ferroptosis. Transfusion and Apheresis Science. 2018 Aug 1;57(4):524–31.

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 Jan 1;13(1):81–90.

Chen X, Li J, Kang R, Klionsky DJ, Tang D. Ferroptosis: machinery and regulation. Vol. 17, Autophagy. Taylor and Francis Ltd.; 2021. p. 2054–81.

Tyurina YY, Shrivastava I, Tyurin VA, Mao G, Dar HH, Watkins S, et al. Only a Life Lived for Others Is Worth Living: Redox Signaling by Oxygenated Phospholipids in Cell Fate Decisions. Vol. 29, Antioxidants and Redox Signaling. Mary Ann Liebert Inc.; 2018. p. 1333–58.

Luo L, Wang H, Tian W, Zeng J, Huang Y, Luo H. Targeting ferroptosis for cancer therapy: iron metabolism and anticancer immunity [Internet]. Vol. 11, Am J Cancer Res. 2021. Available from: www.ajcr.us/

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 Jan 1;13(1):91–8.

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 Jan 1;13(1):81–90.

Wenzel SE, Tyurina YY, Zhao J, St. Croix CM, Dar HH, Mao G, et al. PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell. 2017 Oct 19;171(3):628-641.e26.

Yuan H, Li X, Zhang X, Kang R, Tang D. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. 2016;478(3):1338–43.

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 U S A. 2016 Aug 23;113(34): E4966–75.

Wenzel SE, Tyurina YY, Zhao J, St. Croix CM, Dar HH, Mao G, et al. PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals. Cell. 2017 Oct 19;171(3):628-641.e26.

Li C, Zhang Y, Liu J, Kang R, Klionsky DJ, Tang D. Mitochondrial DNA stress triggers autophagy-dependent ferroptotic death. Autophagy. 2021;17(4):948–60.

Tang D, Chen X, Kang R, Kroemer G. Ferroptosis: molecular mechanisms and health implications. Vol. 31, Cell Research. Springer Nature; 2021. p. 107–25.

Trachootham D, Alexandre J, Huang P. Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Vol. 8, Nature Reviews Drug Discovery. 2009. p. 579–91.

Kapralov AA, Yang Q, Dar HH, Tyurina YY, Anthonymuthu TS, Kim R, et al. Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat Chem Biol. 2020 Mar 1;16(3):278–90.

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 May 25;149(5):1060–72.

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. 2015;

Doll S, Conrad M. Iron and ferroptosis: A still ill-defined liaison. Vol. 69, IUBMB Life. Blackwell Publishing Ltd; 2017. p. 423–34.

Imai H, Matsuoka M, Kumagai T, Sakamoto T, Koumura T. Lipid peroxidation-dependent cell death regulated by GPx4 and ferroptosis. In: Current Topics in Microbiology and Immunology. Springer Verlag; 2017. p. 143–70.

Yanatori I, Kishi F. DMT1 and iron transport. Vol. 133, Free Radical Biology and Medicine. Elsevier Inc.; 2019. p. 55–63.

Fulvio Ursini, Valentina Bosello Travain, Giorgio Cozza, Giovanni Miotto, Antonella Roveri, Stefano Toppo, et al. A white paper on Phospholipid Hydroperoxide Glutathione Peroxidase (GPx4) forty years later. PubMed. 2022 Aug 1;188:117–33.

Shi Y, Shi X, Zhao M, Chang M, Ma S, Zhang Y. Ferroptosis: A new mechanism of traditional Chinese medicine compounds for treating acute kidney injury. Vol. 163, Biomedicine and Pharmacotherapy. Elsevier Masson s.r.l.; 2023.

Shimada K, Hayano M, Pagano NC, Stockwell BR. Cell-Line Selectivity Improves the Predictive Power of Pharmacogenomic Analyses and Helps Identify NADPH as a Biomarker for Ferroptosis Sensitivity. Cell Chem Biol. 2016 Feb 18;23(2):225–35.

Dixon SJ, Patel D, Welsch M, Skouta R, Lee E, Hayano M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. 2014 May 20;2014(3).

Lu B, Chen X bing, Hong Y cai, Zhu H, He Q jun, Yang B, et al. Identification of PRDX6 as a regulator of ferroptosis. Acta Pharmacol Sin. 2019 Oct 1;40(10):1334–42.

Llabani E, Hicklin RW, Lee HY, Motika SE, Crawford LA, Weerapana E, et al. Diverse compounds from pleuromutilin lead to a thioredoxin inhibitor and inducer of ferroptosis. Nat Chem. 2019 Jun 1;11(6):521–32.

Lei P, Bai T, Sun Y. Mechanisms of ferroptosis and relations with regulated cell death: A review. Front Physiol. 2019;10(FEB).

Xie Y, Zhu S, Song X, Sun X, Fan Y, Liu J, et al. The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity. Cell Rep. 2017 Aug 15;20(7):1692–704.

Zhao Y, Li Y, Zhang R, Wang F, Wang T, Jiao Y. The role of Erastin in ferroptosis and its prospects in cancer therapy. Vol. 13, OncoTargets and Therapy. Dove Medical Press Ltd.; 2020. p. 5429–41.

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 Jan 1;13(1):91–8.

Yuan H, Li X, Zhang X, Kang R, Tang D. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. 2016;478(3):1338–43.

Li D, Li Y. The interaction between ferroptosis and lipid metabolism in cancer. Vol. 5, Signal Transduction and Targeted Therapy. Springer Nature; 2020.

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 Jan 1;13(1):81–90.

Magtanong L, Ko PJ, To M, Cao JY, Forcina GC, Tarangelo A, et al. Exogenous Monounsaturated Fatty Acids Promote a Ferroptosis-Resistant Cell State. Cell Chem Biol. 2019 Mar 21;26(3):420-432.e9.

Ubellacker JM, Tasdogan A, Ramesh V, Shen B, Mitchell EC, Martin-Sandoval MS, et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature. 2020 Sep 3;585(7823):113–8.

Hoy AJ, Nagarajan SR, Butler LM. Tumour fatty acid metabolism in the context of therapy resistance and obesity. Vol. 21, Nature Reviews Cancer. Nature Research; 2021. p. 753–66.

Wang H, Liu C, Zhao Y, Gao G. Mitochondria regulation in ferroptosis. Vol. 99, European Journal of Cell Biology. Elsevier GmbH; 2020.

Hu H, Chen Y, Jing L, Zhai C, Shen L. The Link Between Ferroptosis and Cardiovascular Diseases: A Novel Target for Treatment. Front Cardiovasc Med. 2021 Jul 22;8.

Doll S, Freitas FP, Shah R, Aldrovandi M, da Silva MC, Ingold I, et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature. 2019 Nov 28;575(7784):693–8.

Song X, Long D. Nrf2 and Ferroptosis: A New Research Direction for Neurodegenerative Diseases. Vol. 14, Frontiers in Neuroscience. Frontiers Media S.A.; 2020.

Liu Z, Dong W, Yang B, Peng L, Xia X, Pu L, et al. Tetrachlorobenzoquinone-Induced Nrf2 Confers Neuron-like PC12 Cells Resistance to Endoplasmic Reticulum Stress via Regulating Glutathione Synthesis and Protein Thiol Homeostasis. Chem Res Toxicol. 2018 Nov 19;31(11):1230–9.

Fan Z, Wirth AK, Chen D, Wruck CJ, Rauh M, Buchfelder M, et al. Nrf2-keap1 pathway promotes cell proliferation and diminishes ferroptosis. Oncogenesis. 2017;6(8).

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 Jan 1;63(1):173–84.

Hassannia B, Vandenabeele P, Vanden Berghe T. Targeting Ferroptosis to Iron Out Cancer. Vol. 35, Cancer Cell. Cell Press; 2019. p. 830–49.

Jeschke J, O’Hagan HM, Zhang W, Vatapalli R, Calmon MF, Danilova L, et al. Frequent inactivation of Cysteine dioxygenase type 1 contributes to the survival of breast cancer cells and resistance to anthracyclines. Clinical Cancer Research. 2013 Jun 15;19(12):3201–11.

Yang WS, Stockwell BR. Ferroptosis: Death by Lipid Peroxidation. Vol. 26, Trends in Cell Biology. Elsevier Ltd; 2016. p. 165–76.

Wan Seok Yang RSMEWKSRSVSVJHCPACAFSCBCLMBAW gIROTTI, VWCSLSBRS. Regulation of ferroptotic cancer cell death by GPX4. PubMed. 2014 Jan 16;156(1–2):317–31.

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 May 16;26(5):623-633.e9.

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. Vol. 171, Cell. Cell Press; 2017. p. 273–85.

Xie Y, Zhu S, Song X, Sun X, Fan Y, Liu J, et al. The Tumor Suppressor p53 Limits Ferroptosis by Blocking DPP4 Activity. Cell Rep. 2017 Aug 15;20(7):1692–704.

Lou JS, Zhao LP, Huang ZH, Chen XY, Xu JT, TAI WCS, et al. 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. 2021 Jan 1;80.

Geng N, Shi BJ, Li SL, Zhong ZY, Li YC, Xua WL, et al. Knockdown of ferroportin accelerates erastin-induced ferroptosis in neuroblastoma cells. PubMed. 2018 Jun 22;12:3826–36.

Lang X, Green MD, Wang W, Yu J, Choi JE, Jiang L, et al. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov. 2019 Dec 1;9(12):1673–85.

Woo JH, Shimoni Y, Yang WS, Subramaniam P, Iyer A, Nicoletti P, et al. Elucidating Compound Mechanism of Action by Network Perturbation Analysis. Cell. 2015 Jul 18;162(2):441–51.

Shimada K, Skouta R, Kaplan A, Yang WS, Hayano M, Dixon SJ, et al. Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis. Nat Chem Biol. 2016 Jul 1;12(7):497–503.

Abrams RP, Carroll WL, Woerpel KA. Five-Membered Ring Peroxide Selectively Initiates Ferroptosis in Cancer Cells. ACS Chem Biol. 2016 May 20;11(5):1305–12.

Yang M, Liu J, Zhu S, Kroemer G, Klionsky DJ, Lotze MT, et al. Clockophagy is a novel selective autophagy process favoring ferroptosis [Internet]. Vol. 5, Sci. Adv. 2019. Available from: http://advances.sciencemag.org/

Hassannia B, Wiernicki B, Ingold I, Qu F, Van Herck S, Tyurina YY, et al. Nano-targeted induction of dual ferroptotic mechanisms eradicates high-risk neuroblastoma. Journal of Clinical Investigation. 2018 Aug 1;128(8):3341–55.

Xiong H, Wang C, Wang Z, Jiang Z, Zhou J, Yao J. Intracellular cascade activated nanosystem for improving ER+ breast cancer therapy through attacking GSH-mediated metabolic vulnerability. Journal of Controlled Release. 2019 Sep 10;309:145–57.

Chang LC, Chiang SK, Chen SE, Yu YL, Chou RH, Chang WC. Heme oxygenase-1 mediates BAY 11–7085-induced ferroptosis. Cancer Lett. 2018 Mar 1;416:124–37.

Mai TT, Hamaï A, Hienzsch A, Cañeque T, Müller S, Wicinski J, et al. Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat Chem. 2017 Oct 1;9(10):1025–33.

Ma S, Henson ES, Chen Y, Gibson SB. Ferroptosis is induced following siramesine and lapatinib treatment of breast cancer cells. Cell Death Dis. 2016;7(7).

Kang R, Zeng L, Zhu S, Xie Y, Liu J, Wen Q, et al. Lipid Peroxidation Drives Gasdermin D-Mediated Pyroptosis in Lethal Polymicrobial Sepsis. Cell Host Microbe. 2018 Jul 11;24(1):97-108.e4.

Raefsky SM, Furman R, Milne G, Pollock E, Axelsen P, Mattson MP, et al. Deuterated polyunsaturated fatty acids reduce brain lipid peroxidation and hippocampal amyloid β-peptide levels, without discernible behavioral effects in an APP/PS1 mutant transgenic mouse model of Alzheimer’s disease. Neurobiol Aging. 2018 Jun 1;66:165–76.

Beaudoin-Chabot C, Wang L, Smarun A V., Vidović D, Shchepinov MS, Thibault G. Deuterated polyunsaturated fatty acids reduce oxidative stress and extend the lifespan of C. Elegans. Front Physiol. 2019;10(MAY).

Nieva-Echevarría B, Goicoechea E, Guillén MD. Polyunsaturated lipids and vitamin A oxidation during cod liver oil in vitro gastrointestinal digestion. Antioxidant effect of added BHT. Food Chem. 2017 Oct 1;232:733–43.

Sun Z, Tang Z, Yang X, Liu QS, Liang Y, Fiedler H, et al. Perturbation of 3-tert-butyl-4-hydroxyanisole in adipogenesis of male mice with normal and high-fat diets. Science of the Total Environment. 2020 Feb 10;703.

Bersuker K, Hendricks JM, Li Z, Magtanong L, Ford B, Tang PH, et al. The CoQ oxidoreductase FSP1 acts in parallel to GPX4 to inhibit ferroptosis. Nature. 2019 Nov 28;575(7784):688–92.

Probst L, Dächert J, Schenk B, Fulda S. Lipoxygenase inhibitors protect acute lymphoblastic leukemia cells from ferroptotic cell death. Biochem Pharmacol. 2017 Sep 15;140:4152.

Kenny EM, Fidan E, Yang Q, Anthonymuthu TS, New LA, Meyer EA, et al. Ferroptosis Contributes to Neuronal Death and Functional Outcome after Traumatic Brain Injury∗. Crit Care Med. 2019 Mar 1;47(3):410–8.

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 Mar 22;3(3):232–43.

Gregus AM, Dumlao DS, Wei SC, Norris PC, Catella LC, Meyerstein FG, et al. Systematic analysis of rat 12/15-lipoxygenase enzymes reveals a critical role for spinal eLOX3 hepoxilin synthase activity in inflammatory hyperalgesia. FASEB Journal. 2013 May;27(5):1939–49.

Liu Y, Wang W, Li Y, Xiao Y, Cheng J, Jia J. The 5-Lipoxygenase Inhibitor Zileuton Confers Neuroprotection against Glutamate Oxidative Damage by Inhibiting Ferroptosis. Vol. 38, Biol. Pharm. Bull. 1234.

Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and Transferrin Regulate Ferroptosis. Mol Cell. 2015 Jul 16;59(2):298–308.

Gao M, Yi J, Zhu J, Minikes AM, Monian P, Thompson CB, et al. Role of Mitochondria in Ferroptosis. Mol Cell. 2019 Jan 17;73(2):354-363.e3.

Rush T, Liu XQ, Nowakowski AB, Petering DH, Lobner D. Glutathione-mediated neuroprotection against methylmercury neurotoxicity in cortical culture is dependent on MRP1. Neurotoxicology. 2012 Jun;33(3):476–81.

Sha LK, Sha W, Kuchler L, Daiber A, Giegerich AK, Weigert A, et al. Loss of Nrf2 in bone marrow-derived macrophages impairs antigen-driven CD8+ T cell function by limiting GSH and Cys availability. Free Radic Biol Med. 2015 Jun 1;83:77–88.

Wang D, Peng Y, Xie Y, Zhou B, Sun X, Kang R, et al. Antiferroptotic activity of non-oxidative dopamine. Biochem Biophys Res Commun. 2016 Nov 25;480(4):602–7.

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 Jan 28;356(2):971–7.

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 (United States). 2021 Dec 1;23(12):1227–39.

Wychowski. Materials and Methods: Cell lines. Huh7 and PLC/PRF5 cells (hepatocellular carcinoma) were obtained from Dr [Internet]. Available from: http://cancer.sanger.ac.uk/cancergenome/projects/cosmic/

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 the NRF2/GPX4 axis. Cell Death Dis. 2021 May 1;12(5).

Ghosh S. Cisplatin: The first metal-based anticancer drug. Vol. 88, Bioorganic Chemistry. Academic Press Inc.; 2019.

Ghoochani A, Hsu EC, Aslan M, Rice MA, Nguyen HM, Brooks JD, et al. Ferroptosis inducers are a novel therapeutic approach for advanced prostate cancer. Cancer Res. 2021 Mar 1;81(6):1583–94.

He GN, Bao NR, Wang S, Xi M, Zhang TH, Chen FS. Ketamine Induces Ferroptosis of Liver Cancer Cells by Targeting lncRNA PVT1/miR-214-3p/GPX4. PubMed. 2021 Sep 18;15:3965–78.

Tsai Y, Xia C, Sun Z. The Inhibitory Effect of 6-Gingerol on Ubiquitin-Specific Peptidase 14 Enhances Autophagy-Dependent Ferroptosis and Anti-Tumor in vivo and in vitro. Front Pharmacol. 2020 Nov 13;11.

Wen Zhang, Baoping Jiang, Yunxin Liu, Li Xu, Meng Wan. Bufotalin induces ferroptosis in non-small cell lung cancer cells by facilitating the ubiquitination and degradation of GPX4. Elsevier. 2022 Feb 20;180:758.

Li C, Zhang Y, Liu J, Kang R, Klionsky DJ, Tang D. Mitochondrial DNA stress triggers autophagy-dependent ferroptotic death. Autophagy. 2021;17(4):948–60.

O’Dwyer PJ, Hamilton TC, Lacreta FP, Gallo JM, Kilpatrick D, Halbherr T, et al. Phase I Trial of Buthionine Sulfoximine in Combination With Melphalan in Patients With Cancer. Vol. 14, J Clin Oncol. 1996.

Nagpal A, Redvers RP, Ling X, Ayton S, Fuentes M, Tavancheh E, et al. Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2+ve breast cancer metastasis. Breast Cancer Research. 2019 Aug 13;21(1).

Graf H, Jüngst C, Straub G, Dogan S, Hoffmann RT, Jakobs T, et al. Chemoembolization combined with pravastatin improves survival in patients with hepatocellular carcinoma. Digestion. 2008 Nov;78(1):34–8.

Kornblau SM, Banker DE, Stirewalt D, Shen D, Lemker E, Verstovsek S, et al. Blockade of adaptive defensive changes in cholesterol uptake and synthesis in AML by the addition of pravastatin to idarubicin high-dose Ara-C: a phase 1 study. 2007;109:2999–3006. Available from: www.bloodjournal.org

Rodríguez A, Borrás JM, López-Torrecilla J, Algara M, Palacios-Eito A, Gómez-Caamaño A, et al. Demand for radiotherapy in Spain. Vol. 19, Clinical and Translational Oncology. Springer-Verlag Italia s.r.l.; 2017. p. 204–10.

Cobler L, Zhang H, Suri P, Park C, Timmerman LA. xCT inhibition sensitizes tumors to γ-radiation via glutathione reduction. PubMed. 2018 Aug 17;64(9):32280–97.

Pan X, Lin Z, Jiang D, Yu Y, Yang D, Zhou H, et al. Erastin decreases the radioresistance of NSCLC cells partially by inducing GPX4-mediated ferroptosis. Oncol Lett. 2019 Mar 1;17(3):3001–8.

Shibata Y, Yasui H, Higashikawa K, Miyamoto N, Kuge Y. Erastin, a ferroptosis-inducing agent, sensitized cancer cells to X-ray irradiation via glutathione starvation in vitro and in vivo. PLoS One. 2019 Dec 1;14(12).

Po Xu, Ying Wang, Zhe Deng, Zhibo Tan, Xiaojuan Pei. MicroRNA-15a promotes prostate cancer cell ferroptosis by inhibiting GPX4 expression. PMC. 2022 Jan 3;67.

Liu L, Yao H, Zhou X, Chen J, Chen G, Shi X, et al. MiR-15a-3p regulates ferroptosis via targeting glutathione peroxidase GPX4 in colorectal cancer. PubMed. 2022 Mar;61(3):301–10.

Gomaa A, Peng D, Chen Z, Soutto M, Abouelezz K, Corvalan A, et al. Epigenetic regulation of AURKA by miR-4715-3p in upper gastrointestinal cancers. Sci Rep. 2019 Dec 1;9(1).

Deng S hua, Wu D ming, Li L, Liu T, Zhang T, Li J, et al. miR-324-3p reverses cisplatin resistance by inducing GPX4-mediated ferroptosis in lung adenocarcinoma cell line A549. Biochem Biophys Res Commun. 2021 Apr 16;549:5460.

Wei D, Ke YQ, Duan P, Zhou L, Wang CY, Cao P. MicroRNA-302a-3p induces ferroptosis of non-small cell lung cancer cells via targeting ferroportin. Free Radic Res. 2021;55(7):821–30.

Bai T, Liang R, Zhu R, Wang W, Zhou L, Sun Y. MicroRNA-214-3p enhances erastin-induced ferroptosis by targeting ATF4 in hepatoma cells. J Cell Physiol. 2020 Jul 1;235(7–8):5637–48.

Li YZ, Zhu HC, Du Y, Zhao HC, Wang L. Silencing lncRNA SLC16A1-AS1 Induced Ferroptosis in Renal Cell Carcinoma Through miR-143-3p/SLC7A11 Signaling. PubMed. 2022 Jan 21;

Chen C, Zhao J, Liu JN, Sun C. Mechanism and Role of the Neuropeptide LGI1 Receptor ADAM23 in Regulating Biomarkers of Ferroptosis and Progression of Esophageal Cancer. PubMed. 2021 Dec 30;

Gai C, Liu C, Wu X, Yu M, Zheng J, Zhang W, et al. MT1DP loaded by folate-modified liposomes sensitizes erastin-induced ferroptosis via regulating miR-365a-3p/NRF2 axis in non-small cell lung cancer cells. Cell Death Dis. 2020 Sep 1;11(9).

Jiang M, Mo R, Liu C, Wu H. Circ_0000190 sponges miR-382-5p to suppress cell proliferation and motility and promote cell death by targeting ZNRF3 in gastric cancer. PubMed. 2022 Jan 14;

Eling N, Reuter L, Hazin J, Hamacher-Brady A, Brady NR. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells [Internet]. Vol. 2, Oncoscience. 2015. Available from: www.impactjournals.com/oncoscience

Yamaguchi Y, Kasukabe T, Kumakura S. Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis. Int J Oncol. 2018 Mar 1;52(3):1011–22.

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 Nov 1;23(11):7349–59.

Nie J, Lin B, Zhou M, Wu L, Zheng T. Role of ferroptosis in hepatocellular carcinoma. Vol. 144, Journal of Cancer Research and Clinical Oncology. Springer Verlag; 2018. p. 2329–37.

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 Aug 1;64(2):488–500.

Hao S, Yu J, He W, Huang Q, Zhao Y, Liang B, et al. Cysteine Dioxygenase 1 Mediates Erastin-Induced Ferroptosis in Human Gastric Cancer Cells. Neoplasia (United States). 2017 Dec 1;19(12):1022–32.

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 Apr 1;50(2):445–60.

Li Z, Chen L, Chen C, Zhou Y, Hu D, Yang J, et al. Targeting ferroptosis in breast cancer. Vol. 8, Biomarker Research. BioMed Central Ltd; 2020.

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 Oct 4;37(40):5435–50.

Belavgeni A, Bornstein SR, Von Mässenhausen A, Tonnus W, Stumpf J, Meyer C, et al. Exquisite sensitivity of adrenocortical carcinomas to the induction of ferroptosis. Proc Natl Acad Sci U S A. 2019 Oct 29;116(44):22269–74.

Greenshields AL, Shepherd TG, Hoskin DW. Contribution of reactive oxygen species to ovarian cancer cell growth arrest and killing by the anti-malarial drug artesunate. Mol Carcinog. 2017 Jan 1;56(1):75–93.

Basuli D, Tesfay L, Deng Z, Paul B, Yamamoto Y, Ning G, et al. Iron addiction: A novel therapeutic target in ovarian cancer. Oncogene. 2017 Jul 20;36(29):4089–99.

Luo M, Wu L, Zhang K, Wang H, Zhang T, Gutierrez L, et al. miR-137 regulates ferroptosis by targeting glutamine transporter SLC1A5 in melanoma. Cell Death Differ. 2018 Aug 1;25(8):1457–72.

Basit F, Van Oppen LMPE, Schöckel L, Bossenbroek HM, Van Emst-De Vries SE, Hermeling JCW, et al. Mitochondrial complex I inhibition triggers a mitophagy-dependent ROS increase, leading to necroptosis and ferroptosis in melanoma cells. Cell Death Dis. 2017;8(3).

Shin D, Kim EH, Lee J, Roh JL. Nrf2 inhibition reverses resistance to GPX4 inhibitor-induced ferroptosis in head and neck cancer. Free Radic Biol Med. 2018 Dec 1;129:454–62.

Roh JL, Kim EH, Jang H, Shin D. Nrf2 inhibition reverses the resistance of cisplatin-resistant head and neck cancer cells to artesunate-induced ferroptosis. Redox Biol. 2017 Apr 1;11:254–62.

Kim EH, Shin D, Lee J, Jung AR, Roh JL. CISD2 inhibition overcomes resistance to sulfasalazine-induced ferroptotic cell death in head and neck cancer. Cancer Lett. 2018 Sep 28;432:180–90.

Czarnecka AM, Synoradzki K, Firlej W, Bartnik E, Sobczuk P, Fiedorowicz M, et al. Molecular biology of osteosarcoma. Vol. 12, Cancers. MDPI AG; 2020. p. 1–27.

Chen Y, Fan Z, Hu S, Lu C, Xiang Y, Liao S. Ferroptosis: A New Strategy for Cancer Therapy. Vol. 12, Frontiers in Oncology. Frontiers Media S.A.; 2022.

Wu H, Zhang J, Dai R, Xu J, Feng H. Transferrin receptor-1 and VEGF are prognostic factors for osteosarcoma. J Orthop Surg Res. 2019 Sep 4;14(1).

Published

2025-08-15

How to Cite

Shrabani Manna, Ayushi Patel, & Dr. Gajendra Singh Tyagi. (2025). Ferroptosis Unleashed: A Bold Approach to Revolutionize Cancer Treatment. Asian Journal of Pharmaceutical Research and Development, 13(4), 68–83. https://doi.org/10.22270/ajprd.v13i4.1597