Spermine is an endogenous iron chelator that inhibits ferroptosis

  • Nature. 2026 Jul;655(8121):240-250. doi: 10.1038/s41586-026-10597-2.
Man Li  1  2 ,  Xuexin Yu  2 ,  Shuqin Ouyang  2 ,  Xiaohong Chen  2 ,  Huiqi Yu  2 ,  Yuanji Liu  2 ,  Ziwen Li  2 ,  Chunhua Yu  3 ,  Rui Kang  3 ,  Christine Gaillet  4 ,  Ludovic Colombeau  4 ,  Raphaël Rodriguez  4 ,  Libing Song  5 ,  Guido Kroemer  6  7  8  9 ,  Daolin Tang  10 ,  Jun Li  11  12
Affiliations
  • 1. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 2. Department of Biochemistry, Zhongshan School of Medicine Sun Yat-sen University, Guangzhou, China.
  • 3. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA.
  • 4. Institut Curie, CNRS, INSERM, PSL Research University, Paris, France.
  • 5. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 6. Université Paris Cité, Sorbonne Université, INSERM, Centre de Recherche des Cordeliers, Paris, France. [email protected].
  • 7. Université Paris-Saclay, INSERM US23/CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. [email protected].
  • 8. Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. [email protected].
  • 9. Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Institut Universitaire de France, Paris, France. [email protected].
  • 10. Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA. [email protected].
  • 11. State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. [email protected].
  • 12. Department of Biochemistry, Zhongshan School of Medicine Sun Yat-sen University, Guangzhou, China. [email protected].
PMID: 42236947 DOI: 10.1038/s41586-026-10597-2
Abstract

Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation1. Here we identify spermine-a polyamine derived from spermidine2-as an endogenous iron chelator that directly suppresses Ferroptosis. Integrating metabolomics, stable isotope tracing and biophysical studies of the interaction between spermine and Fe2+ ions, we demonstrate that aldehyde dehydrogenase 18 family member A1 (ALDH18A1) promotes an alternative glutamine-dependent pathway for de novo spermine synthesis. This process limits iron availability and lipid peroxidation in hepatocellular carcinoma. Genetic or pharmacological inhibition of ALDH18A1-through knockout, short hairpin RNA delivered using adeno-associated virus (AAV), or the small molecule inhibitor YG1702-triggers Ferroptosis and impairs both spontaneous and chemically induced hepatocarcinogenesis. Conversely, supplementation of spermine protects against ferroptosis-associated ischaemia-reperfusion injury across multiple tissues, including the liver, intestine and kidneys. These findings uncover a pathophysiologically relevant metabolic circuit in which spermine-mediated iron chelation suppresses Ferroptosis.

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