In a recent study published in Nature it was discovered that the polyamine spermine acts as a chelator of intracellular iron and thus as a suppressor of ferroptosis. Spermine is a polyamine metabolite that is essential for cellular homeostasis, with known roles ranging from DNA stabilization and RNA processing to protein synthesis and ion channel regulation. Dysregulation of spermine metabolism is implicated in various malignant, neurodegenerative and inflammatory diseases.

Ferroptosis is a distinct form of programmed cell death that involves intracellular accumulation of redox-active iron, formation of reactive oxygen species (ROS) and peroxidation of phospholipids, ultimately resulting in dysregulation and rupture of cellular membranes. Dysregulated ferroptosis contributes to human diseases such as cancer, neurodegeneration and cardiovascular disease. Inducing or inhibiting ferroptosis using small molecules has emerged as a hotspot for research around treatment of these diseases, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored.

The study by Li et al. demonstrated that in the liver, which is the major organ for systemic iron storage, ferroptosis serves a tumor suppressive role, with evasion of ferroptosis serving an important role in malignant transformation. In HCC, a disease associated with major metabolic rewiring, biosynthesis of polyamines is the most upregulated metabolic pathway. As it turns out, specifically spermine has an important role in tumor development by acting as an intracellular chelator for labile Fe2+ ions. When spermine binds Fe2+, the formation of a redox-inactive complex suppresses lipid peroxidation and thus inhibits ferroptosis.

Interestingly, the upregulation of polyamine metabolism in HCC turns out to be driven by the mitochondrial enzyme ALDH18A1. ALDH18A1 is involved in synthesis of polyamines through a non-canonical glutaminolysis-dependent pathway, which is independent of the urea cycle. In agreement, inhibition of ALDH18A1 suppressed hepatocarcinogenesis through depletion of spermine and activation of ferroptosis in HCC, opening up new opportunities for disease intervention.