Cancer cells have found an entirely new way to cheat death: they hijack a metabolic pathway to produce a molecule that literally mops up free iron, preventing a form of cell death called ferroptosis. The strategy uses spermine, a polyamine already abundant in the body, but repurposes it as a direct iron chelator through a biochemical pathway that cancer cells turbocharge.
The finding, published in Nature by a team led by Jun Li at Guangzhou Medical University and collaborators across China, France, and the United States, reveals a ferroptosis defense mechanism that is biophysically, not enzymatically, driven. Spermine binds ferrous iron (Fe2+) directly, starving the Fenton reaction that would otherwise produce the lipid peroxides that kill ferroptotic cells.
It is the first time an endogenous metabolite has been shown to block ferroptosis through pure chemical chelation, rather than through an enzymatic pathway like the well-known GPX4, FSP1, or GCH1 systems.
The spermine switch
Spermine is a naturally occurring polyamine synthesized from the amino acid arginine via ornithine. It is involved in cell proliferation, differentiation, and ion channel modulation. What the Li team discovered is that cancer cells, particularly hepatocellular carcinoma (HCC), dramatically upregulate the enzyme ALDH18A1, which funnels glutamine into an alternative, de novo spermine synthesis pathway.
Using 13C and 15N isotope tracing, the researchers showed that ALDH18A1 diverts glutamine-derived carbon and nitrogen toward ornithine and then polyamines, bypassing the standard polyamine biosynthesis route. The result is a massive surge in intracellular spermine, which then binds free iron with micromolar affinity, confirmed by isothermal titration calorimetry, Raman spectroscopy, NMR, and cyclic voltammetry.
In a series of cell-based experiments, spermine rescued cancer cells from every major class of ferroptosis inducer tested: RSL3, erastin, FIN56, FINO2, and cystine starvation. The protection was independent of GPX4, FSP1, GCH1, and glutathione levels, placing this mechanism on an entirely separate axis from the known ferroptosis defense network.
ALDH18A1 as a therapeutic target
The study used genetic knockout, AAV-delivered short hairpin RNA, and a small-molecule inhibitor called YG1702 to suppress ALDH18A1 in mouse models of HCC. In both spontaneous (L/Tsc1/Pten knockout) and chemically induced (DEN/CCl4) liver cancer models, ALDH18A1 inhibition triggered ferroptosis and suppressed hepatocarcinogenesis. The effect was reversed by co-administering either spermine or liproxstatin-1, a ferroptosis inhibitor, confirming the mechanistic link.
Clinically, the researchers examined human HCC tissue banks and found that high ALDH18A1 expression correlated with elevated polyamine levels and significantly worse patient survival. This suggests that the ALDH18A1-spermine-ferroptosis axis is active in human disease, not just in mouse models.
Beyond cancer, the team found that a single 1 mg/kg dose of spermine protected mice from ischemia-reperfusion injury in the liver, intestine, and kidney, reducing biomarkers such as ALT, AST, LDH, BUN, and serum creatinine. This raises the possibility that spermine supplementation, or modulation of the ALDH18A1 pathway, could have applications in organ preservation and transplant medicine.
A parallel defense, not a replacement
The discovery adds a new layer to the growing understanding of ferroptosis resistance. Cancer cells do not rely on a single defense; they layer multiple parallel systems. The Li team’s finding means that therapeutic strategies targeting ferroptosis will need to account for this polyamine-based chelation pathway alongside the traditional enzymatic defenses.
But several caveats apply. All in vivo tumor work was done in mice; no clinical trials of ALDH18A1 inhibitors have been conducted in humans. The small molecule YG1702 is a tool compound with unknown pharmacokinetics, toxicity, and selectivity in humans. ALDH18A1 also participates in proline biosynthesis (it is a P5CS enzyme), so inhibiting it could have off-target effects on collagen metabolism, wound healing, and redox balance beyond polyamine synthesis.
Additionally, the study was conducted in hepatocellular carcinoma specifically. Whether the ALDH18A1-spermine-ferroptosis axis operates similarly in breast, lung, colon, or other cancers remains unknown. Given that multiple ferroptosis defense systems can coexist, targeting just one, even a novel one, may not be sufficient for durable therapeutic responses.
Spermine itself also has a dual nature. It promotes cell proliferation and has known signaling roles. Chronic systemic elevation for ischemic protection could carry unintended pro-tumorigenic risks.
What’s next
The Li lab and collaborators are now working on developing more selective ALDH18A1 inhibitors with drug-like properties. The team is also investigating whether the same pathway operates in other cancer types and whether spermine levels could serve as a biomarker for ferroptosis resistance in clinical samples.
Source: Li, M., Yu, X., Ouyang, S. et al. Spermine is an endogenous iron chelator that inhibits ferroptosis. Nature (2026). DOI: 10.1038/s41586-026-10597-2