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0This research article identifies polyamines as essential endogenous buffers that regulate iron homeostasis and prevent ferroptosis, a form of iron-dependent cell death. Using a genome-wide CRISPR screen, the authors discovered that depleting these metabolites creates a synthetic lethal dependency with the antioxidant enzyme GPX4. Mechanistically, the loss of spermine and spermidine increases the labile iron pool, which heightens lipid peroxidation and cellular vulnerability to oxidative stress. The study demonstrates that polyamines directly coordinate Fe2+ to limit its reactivity, repositioning these abundant metabolites as key regulators of cellular redox balance. These findings suggest that maintaining millimolar concentrations of polyamines is a critical evolutionary strategy for suppressing iron-driven toxicity in mammalian cells.
References:
Sharma P, Keys H R, Mansell R P, et al. Polyamines buffer labile iron to suppress ferroptosis[J]. Cell, 2026.
