Spermine is an endogenous iron chelator that inhibits ferroptosis

Ferroptosis is an iron-dependent form of cell death driven by lipid peroxidation. Here, we identify spermine—a polyamine derived from spermidine—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, thereby limiting iron availability and lipid peroxidation in hepatocellular carcinoma. Genetic or pharmacological inhibition of ALDH18A1—by knockout, AAV-delivered shRNA, or the small molecule inhibitor YG1702—triggers ferroptosis and impairs both spontaneous and chemically induced hepatocarcinogenesis. Conversely, supplementation of spermine protects against ferroptosis-associated ischemia–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.