Ferroptosis, a key to unravel the enigma of the FLASH effect?

Ferroptosis is a non-apoptotic form of cell death dependent on iron and lipid peroxides. It has been recently described to have a role on cell death after radiation (RT) through a DNA damage independent mechanism. While the modification of ferroptosis pathways is suggested to enhance radiosensitisation, normal tissue toxicity may limit the combined treatment of RT and ferroptosis inducers. FLASH RT is given at ultra-high dose rates to reduce normal tissue toxicities, which contributes to the RT effect on the tumour. Although several hypotheses including oxygen depletion, reduced ROS, and immune responses are suggested to explain the FLASH effect, the underlying mechanisms of normal tissue sparing effects are still not well understood. Previous studies highlighting the inverse effect of RT dose rates and lipid peroxidation, along with the hypothesis by Spitz et al, suggest that oxygen depletion from the chain reaction of lipid peroxidation and differences in labile pool between normal and tumour tissues may be related to the normal tissue sparing effect of FLASH. Therefore, the role of ferroptosis in ultra-high dose rate FLASH RT needs to be investigated further as it might be the key to increase the therapeutic window of FLASH RT.