Spermine identified as endogenous iron chelator that inhibits ferroptosis in hepatocellular carcinoma (nature.com)

• Spermine directly chelates Fe2+ ions, acting as an endogenous ferroptosis suppressor.
• ALDH18A1 drives a glutamine-dependent alternative pathway for spermine synthesis in HCC.
• Inhibition of ALDH18A1 induces ferroptosis and reduces hepatocarcinogenesis; spermine supplementation protects against ischemia-reperfusion injury.

"A study published in Nature identifies spermine as an endogenous iron chelator that directly suppresses ferroptosis. Using metabolomics, stable isotope tracing, and biophysical assays, researchers demonstrate that aldehyde dehydrogenase 18 family member A1 (ALDH18A1) promotes an alternative glutamine-dependent pathway for spermine synthesis, limiting iron availability and lipid peroxidation in hepatocellular carcinoma (HCC). Genetic or pharmacological inhibition of ALDH18A1 triggers ferroptosis and suppresses hepatocarcinogenesis in mouse models. Conversely, spermine supplementation protects against ferroptosis-associated ischemia-reperfusion injury in the liver, intestine, and kidneys, revealing a therapeutic target for ferroptosis-related diseases."