Thursday, June 4, 2026
No menu items!
HomeNatureSpermine is an endogenous iron chelator that inhibits ferroptosis

Spermine is an endogenous iron chelator that inhibits ferroptosis

  • Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Madeo, F., Eisenberg, T., Pietrocola, F. & Kroemer, G. Spermidine in health and disease. Science 359, eaan2788 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Cañeque, T. et al. Activation of lysosomal iron triggers ferroptosis in cancer. Nature 642, 492–500 (2025).

  • Dai, E. et al. A guideline on the molecular ecosystem regulating ferroptosis. Nat. Cell Biol. 26, 1447–1457 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, F., Kang, R., Tang, D. & Liu, J. Ferroptosis: principles and significance in health and disease. J. Hematol. Oncol. 17, 41 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Stockwell, B. R. et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171, 273–285 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brown, A. R., Hirschhorn, T. & Stockwell, B. R. Ferroptosis-disease perils and therapeutic promise. Science 386, 848–849 (2024).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

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

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, Y. et al. 7-Dehydrocholesterol dictates ferroptosis sensitivity. Nature 626, 411–418 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Freitas, F. P. et al. 7-Dehydrocholesterol is an endogenous suppressor of ferroptosis. Nature 626, 401–410 (2024).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Fakler, B. et al. Strong voltage-dependent inward rectification of inward rectifier K+ channels is caused by intracellular spermine. Cell 80, 149–154 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ficker, E., Taglialatela, M., Wible, B. A., Henley, C. M. & Brown, A. M. Spermine and spermidine as gating molecules for inward rectifier K+ channels. Science 266, 1068–1072 (1994).

    Article 
    ADS 
    CAS 
    PubMed 

    Google Scholar
     

  • Zabala-Letona, A. et al. Polyamine-dependent metabolic shielding regulates alternative splicing. Nature 651, 819–828 (2026).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hofer, S. J. et al. Spermidine is essential for fasting-mediated autophagy and longevity. Nat. Cell Biol. 26, 1571–1584 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eisenberg, T. et al. Cardioprotection and lifespan extension by the natural polyamine spermidine. Nat. Med. 22, 1428–1438 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Kang, R., Liu, J., Wang, J., Kroemer, G. & Tang, D. Translating ferroptosis into oncology: challenges, opportunities and future directions. Nat. Rev. Clin. Oncol. https://doi.org/10.1038/s41571-026-01128-z (2026).

  • Guri, Y. et al. mTORC2 promotes tumorigenesis via lipid synthesis. Cancer Cell 32, 807–823 (2017).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dapito, D. H. et al. Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21, 504–516 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, X. et al. The immunological and metabolic landscape in primary and metastatic liver cancer. Nat. Rev. Cancer 21, 541–557 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Casero, R. A. Jr., Murray Stewart, T. & Pegg, A. E. Polyamine metabolism and cancer: treatments, challenges and opportunities. Nat. Rev. Cancer 18, 681–695 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zabala-Letona, A. et al. mTORC1-dependent AMD1 regulation sustains polyamine metabolism in prostate cancer. Nature 547, 109–113 (2017).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bi, G. et al. Polyamine-mediated ferroptosis amplification acts as a targetable vulnerability in cancer. Nat. Commun. 15, 2461 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bae, H. et al. Ferroptosis-activating metabolite acrolein antagonizes necroptosis and anti-cancer therapeutics. Nat. Commun. 16, 4919 (2025).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sava, I. G., Battaglia, V., Rossi, C. A., Salvi, M. & Toninello, A. Free radical scavenging action of the natural polyamine spermine in rat liver mitochondria. Free Radic. Biol. Med. 41, 1272–1281 (2006).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Mai, T. T. et al. Salinomycin kills cancer stem cells by sequestering iron in lysosomes. Nat. Chem. 9, 1025–1033 (2017).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, M. S. et al. Ornithine aminotransferase supports polyamine synthesis in pancreatic cancer. Nature 616, 339–347 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pérez-Arellano, I., Carmona-Alvarez, F., Martínez, A. I., Rodríguez-Díaz, J. & Cervera, J. Pyrroline-5-carboxylate synthase and proline biosynthesis: from osmotolerance to rare metabolic disease. Protein Sci. 19, 372–382 (2010).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Luan, X. et al. Ferroptosis in organ ischemia–reperfusion injuries: recent advancements and strategies. Mol. Cell. Biochem. 480, 19–41 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Omer, A. K., Mohammed, R. R., Ameen, P. S. M., Abas, Z. A. & Ekici, K. Presence of biogenic amines in food and their public health implications: a review. J. Food Prot. 84, 1539–1548 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Zhao, Y. J. et al. Role of polyamines in myocardial ischemia/reperfusion injury and their interactions with nitric oxide. Eur. J. Pharmacol. 562, 236–246 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hino, K., Yanatori, I., Hara, Y. & Nishina, S. Iron and liver cancer: an inseparable connection. FEBS J. 289, 7810–7829 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sun, J. et al. Fatty acid binding protein 5 suppression attenuates obesity-induced hepatocellular carcinoma by promoting ferroptosis and intratumoral immune rewiring. Nat. Metab. 6, 741–763 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, M. et al. S100P is a ferroptosis suppressor to facilitate hepatocellular carcinoma development by rewiring lipid metabolism. Nat. Commun. 16, 509 (2025).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, X. et al. A noncanonical function of EIF4E limits ALDH1B1 activity and increases susceptibility to ferroptosis. Nat. Commun. 13, 6318 (2022).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, J. S. et al. ALDH7A1 protects against ferroptosis by generating membrane NADH and regulating FSP1. Cell 188, 2569–2585 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tang, D., Kroemer, G. & Kang, R. Targeting cuproplasia and cuproptosis in cancer. Nat. Rev. Clin. Oncol. 21, 370–388 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Sharma, P. et al. Polyamines buffer labile iron to suppress ferroptosis. Preprint at bioRxiv https://doi.org/10.1101/2025.06.30.662349 (2025).

  • Liu, J. et al. Extracellular GPX4 impairs antitumor immunity via dendritic ZP3 receptors. Cell 189, 1056–1073 (2026).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Jiang, S. et al. Generic Diagramming Platform (GDP): a comprehensive database of high-quality biomedical graphics. Nucleic Acids Res. 53, D1670–D1676 (2025).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gu, Y. et al. Circular RNA circIPO11 drives self-renewal of liver cancer initiating cells via Hedgehog signaling. Mol. Cancer 20, 132 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Takami, Y. et al. Systemic aldehyde storm induced by allyl alcohol exposure results in extensive hepatic ferroptosis in Aldh2*2 knock-in mice. Free Radic. Biol. Med. 239, 177–188 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Domijan, A. M., Ralic, J., Radic Brkanac, S., Rumora, L. & Zanic-Grubisic, T. Quantification of malondialdehyde by HPLC-FL—application to various biological samples. Biomed. Chromatogr. 29, 41–46 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shah, R., Farmer, L. A., Zilka, O., Van Kessel, A. T. M. & Pratt, D. A. Beyond DPPH: use of fluorescence-enabled inhibited autoxidation to predict oxidative cell death rescue. Cell Chem. Biol. 26, 1594–1607 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Poulin, R., Coward, J. K., Lakanen, J. R. & Pegg, A. E. Enhancement of the spermidine uptake system and lethal effects of spermidine overaccumulation in ornithine decarboxylase-overproducing L1210 cells under hyposmotic stress. J. Biol. Chem. 268, 4690–4698 (1993).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pall, A. E. et al. ATH434, a promising iron-targeting compound for treating iron regulation disorders. Metallomics 16, mfae044 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sztula, A., Antal, P., Nemec, I., Kubala, M. & Herchel, R. A novel type of heteroleptic Cu(I) complexes featuring nitrogen-rich tetrazine ligands: syntheses, crystal structures, spectral properties, cyclic voltammetry, and theoretical calculations. Dalton Trans. 54, 5944–5952 (2025).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, Z. et al. LPCAT1-mediated membrane phospholipid remodelling promotes ferroptosis evasion and tumour growth. Nat. Cell Biol. 26, 811–824 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, H. et al. YAP/TAZ drives cell proliferation and tumour growth via a polyamine–eIF5A hypusination–LSD1 axis. Nat. Cell Biol. 24, 373–383 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Horie, Y. et al. Hepatocyte-specific Pten deficiency results in steatohepatitis and hepatocellular carcinomas. J. Clin. Invest. 113, 1774–1783 (2004).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fang, X. et al. Malic enzyme 1 as a novel anti-ferroptotic regulator in hepatic ischemia/reperfusion injury. Adv. Sci. 10, e2205436 (2023).

    Article 

    Google Scholar
     

  • Deng, F. et al. The gut microbiota metabolite capsiate promotes Gpx4 expression by activating TRPV1 to inhibit intestinal ischemia reperfusion-induced ferroptosis. Gut Microbes 13, 1–21 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, X. et al. Small extracellular vesicles delivering lncRNA WAC-AS1 aggravate renal allograft ischemia–reperfusion injury by inducing ferroptosis propagation. Cell Death Differ. 30, 2167–2186 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, R. et al. FTO deficiency in older livers exacerbates ferroptosis during ischaemia/reperfusion injury by upregulating ACSL4 and TFRC. Nat. Commun. 15, 4760 (2024).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, W. et al. Exosomal circEZH2_005, an intestinal injury biomarker, alleviates intestinal ischemia/reperfusion injury by mediating Gprc5a signaling. Nat. Commun. 14, 5437 (2023).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Minami, K. et al. Targeting of intragraft reactive oxygen species by APP-103, a novel polymer product, mitigates ischemia/reperfusion injury and promotes the survival of renal transplants. Am. J. Transplant. 20, 1527–1537 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vaidya, V. S. et al. Kidney injury molecule-1 outperforms traditional biomarkers of kidney injury in preclinical biomarker qualification studies. Nat. Biotechnol. 28, 478–485 (2010).

    Article 
    ADS 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • RELATED ARTICLES

    Most Popular

    Recent Comments