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Man Li^1,2, Xuexin Yu², Shuqin Ouyang², Xiaohong Chen², Huiqi Yu², Yuanji Liu², Ziwen Li², Chunhua Yu³, Rui Kang³, Christine Gaillet⁴, Ludovic Colombeau⁴, Raphaël Rodriguez⁴, Libing Song¹ ✉, Guido Kroemer^5,6,7,8 ✉, Daolin Tang³ ✉ & Jun Li^1,2 ✉

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.

Ferroptosis is an iron-dependent, non-apoptotic form of cell death char- acterized by reactive oxygen species (ROS) accumulation and excessive lipid peroxidation¹. Canonical ferroptosis inducers, such as erastin and RSL3, target the pathway that comprises solute carrier family 7 member 11 (SLC7A11), glutathione (GSH) and glutathione peroxidase 4 (GPX4). Conversely, ferroptosis can be inhibited by antioxidant small molecules such as deferoxamine (DFO), ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1), or promoted by iron-activating compounds^3,4. Dysregulated ferroptosis contributes to diseases ranging from cancer to ischaemia– reperfusion injury^4–7. In addition to the GPX4 pathway⁸, several GPX4- independent defence mechanisms exist, including ferroptosis sup- pressor protein 1 (FSP1; also known as AIFM2)^9,10 and metabolic antioxidants such as 7-dehydrocholesterol^11,12. However, the role of endogenous iron-chelating metabolites in ferroptosis remains to be fully elucidated. Spermine is a ubiquitous polyamine essential for cellular homeostasis, and it contributes to DNA stabilization, RNA pro- cessing, protein synthesis and ion channel regulation^13–15. It is synthesized from spermidine by spermine synthase, and its con- centrations in cells and tissues are regulated through coordinated pathways of synthesis, degradation and transport. Together with spermidine, spermine supports cell growth, stress adaptation and longevity^16–18. Dysregulation of spermine metabolism is impli- cated in various malignant, neurodegenerative and inflammatory diseases².

Here using genetic and carcinogen-induced models of hepatocel- lular carcinoma (HCC), we identify spermine as a key endogenous iron chelator that inhibits ferroptosis. We further uncover an alterna- tive ALDH18A1-mediated spermine biosynthesis pathway. Targeting this metabolic axis suppresses hepatocarcinogenesis and allevi- ates ischaemia–reperfusion injury, thus highlighting the therapeutic potential of modulating spermine metabolism.

The role of ferroptosis in tumorigenesis depends on the context. That is, it varies with genetic alterations, the tumour microenviron- ment and disease stage¹⁹. To clarify its role in HCC, we analysed two complementary mouse models. The first model involves knocking out hepatocyte-specific Tsc1 (which encodes TSC complex subunit 1) and Pten (which encodes phosphatase and tensin homologue) to cre- ate L-Tsc1^−/−Pten^−/− mice²⁰. These mice develop HCC that is driven by metabolic dysfunction-associated steatohepatitis (MASH; previously known as NASH). The second model involves treating mice with dieth- ylnitrosamine (DEN) and carbon tetrachloride (CCl₄) (DEN/CCl₄) to induce fibrosis-associated HCC²¹ (Fig. 1a,b and Supplementary Fig. 1a).

To track disease progression and ferroptosis dynamics, we collected liver tissue samples from L-Tsc1^−/−Pten^−/− mice at 3, 6, 16 and 20 weeks, timings that represent stages of normal liver, hepatomegaly, steato- hepatitis and HCC, respectively. In parallel, liver tissue samples from

https://doi.org/10.1038/s41586-026-10597-2

Received: 18 May 2025 Accepted: 27 April 2026 Published online: xx xx xxxx

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¹State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. ²Department of Biochemistry, Zhongshan School of Medicine Sun Yat-sen University, Guangzhou, China. ³Department of Surgery, UT Southwestern Medical Center, Dallas, TX, USA. ⁴Institut Curie, CNRS, INSERM, PSL Research University, Paris, France. ⁵Université Paris Cité, Sorbonne Université, INSERM, Centre de Recherche des Cordeliers, Paris, France. ⁶Université Paris-Saclay, INSERM US23/CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. ⁷Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. ⁸Centre de Recherche des Cordeliers, Equipe Labellisée par la Ligue Contre le Cancer, Institut Universitaire de France, Paris, France.

✉e-mail: songlb@sysucc.org.cn; kroemer@orange.fr; daolin.tang@utsouthwestern.edu; lijun37@mail.sysu.edu.cn

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