Polyamines buffer labile iron to suppress ferroptosis
Name
Sharma_Ferroptosis_2026.pdf
Description
Accepted version
Size
15.37 MB
Format
Adobe PDF
Checksum (MD5)
ead730a6f0f4553fca62010a6bbf0831
Author(s)
Sharma, Pushkal
Keys, Heather R
Mansell, Ryan P
Stark, Jillian
Girard, Louisa
Ausler, Christalyn
Anderson, Rachel
Müller, Sebastian
Imada, Shinya
Pires, Ivan S
Date Issued
August 2026
Journal
Cell
Publisher
Elsevier BV
Citation
Sharma P, Keys H, Mansell R et al. Polyamines buffer labile iron to suppress ferroptosis. Cell, 2026.
Version
Author's final manuscript
Abstract
Polyamines are essential and evolutionarily conserved metabolites present at millimolar concentrations in mammalian cells. Cells tightly regulate polyamine homeostasis through complex feedback mechanisms, yet the precise role necessitating this regulation remains unclear. Here, we show that polyamines contribute to endogenous buffering of redox-active iron, providing a molecular link between polyamine metabolism and ferroptosis. Using a genome-wide CRISPR screen, we identified a synthetic lethal dependency between polyamine depletion and the key ferroptosis suppressor, glutathione peroxidase 4 (GPX4). Mechanistically, we show that polyamine deficiency triggers a redistribution of cellular iron, increasing the labile iron pool and upregulating ferritin. To directly visualize this iron buffering in living cells, we developed a genetically encoded fluorescent reporter for redox-active iron. Live-cell analysis revealed a striking inverse correlation between intracellular polyamine levels and redox-active iron at single-cell resolution. These findings reposition polyamines as key regulators of iron homeostasis, with implications for ferroptosis-linked disease states and cellular redox balance.
MIT Department
Whitehead Institute for Biomedical Research
Terms of Use
Creative Commons Attribution-NonCommercial-NoDerivatives
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1016/j.cell.2026.07.040
