Researchers in the Department of Oncology have uncovered new insights into how FLASH radiation therapy (RT) kills cancer cells while minimising damage to healthy tissues. The study, led by Dr Ejung Moon in collaboration with Dr Kristoffer Petersson, has demonstrated that FLASH RT induces iron-dependent cell death in tumour cells but not in healthy cells, which may contribute to its tissue sparing effect. Notably, tissue iron levels were shown to critically influence this process, opening new avenues of investigation into which cancer types may benefit most from this promising therapeutic technique.
Radiation therapy (RT) is a mainstay of cancer treatment, with around 50% of all patients receiving RT as part of their treatment plan. While advances in technology have led to significant improvements in precision and effectiveness, the unintended damage to nearby healthy tissues is one of the major limitations of its use. This damage can cause lasting effects and, in some cases, forces treatment to stop early. A key research goal has therefore been to develop novel RT technologies capable of maintaining tumour killing rates, while reducing harm to healthy tissues.
FLASH radiation kills tumour cells while sparing healthy tissues
FLASH RT is a new technique that delivers radiation thousands of times faster than conventional methods. This ultra-high dose rate RT kills cancer cells while selectively minimising damage to healthy tissues – a phenomenon known as the FLASH effect. The precise mechanisms underlying the tissue sparing FLASH effect are yet to be fully explained, but changes in numerous molecular processes are thought to be involved, including temporary oxygen depletion from cells and immune system changes. With the successfully established FLASH radiation setup led by the Petersson group, Dr Moon and her research group explored the potential role of iron in the FLASH effect.
The importance of iron in cell survival
Our cells are highly dependent on iron for numerous critical functions, including oxygen transportation, energy production, and DNA synthesis. As cancer cells grow and replicate so rapidly, they are even more reliant on iron for their survival; significant increases in iron levels can be seen in the blood and tissues of patients with cancer. Importantly, this increased iron dependency makes cancer cells more vulnerable to ferroptosis: a type of programmed cell death driven by iron-dependent lipid peroxidation, where high iron levels trigger reactions that damage the fatty cell membrane and compromise its integrity.
Although RT is well-known to induce DNA damage as its primary mechanism of action, recent evidence shows that it also promotes ferroptosis to kill cells. Therefore, the research team wanted to investigate the potential role of ferroptosis in the FLASH effect, hypothesising that differences in iron levels between cancer and healthy cells would contribute to the difference in activity.
FLASH RT triggers tumour-specific lipid peroxidation
To investigate this, the team compared the impact of conventional and FLASH RT in cancer cell lines and tumour tissues from lung cancer mouse models. They observed comparable increases in lipid peroxidation levels with both techniques, consistent with ferroptosis activation. However, the effects on healthy tissues were strikingly different. Conventional RT resulted in significantly increased lipid peroxidation levels in healthy lung tissues, while the same dose of FLASH RT caused markedly reduced lipid peroxidation levels in comparison. This difference suggests that reduced lipid peroxidation in normal tissues may be a key reason for the protective FLASH effect.
Dr Moon and her team then examined whether differences in the iron levels seen in tumour tissues and healthy tissues could explain these opposing effects. Mice were fed high iron diets for varying amounts of time and treated with either conventional or FLASH RT. When using conventional RT, lipid peroxidation levels were highly increased irrespective of the amount of iron in their diet.
In mice on a standard or short-term high-iron diet, FLASH RT did not increase lipid peroxidation significantly, compared to conventional RT. However, in mice fed a high-iron diet for 96 hours, the protective FLASH effect was lost: lipid peroxidation levels rose to those seen with conventional RT.
Showing a comparable pattern, the amount of damage to small intestine crypts was significantly lower when using FLASH versus conventional RT in mice on a standard or short-term high-iron diet. In mice receiving a 96-hour high-iron diet, this protection was lost.
By raising iron levels in healthy tissue, the tissue sparing effects of FLASH were reversed, demonstrated by the increase in lipid peroxidation levels. This suggests that iron availability in normal cells versus cancer cells plays a crucial role in the FLASH effect - Ejung Moon, Lead author
These data provide new mechanistic insights into FLASH RT, indicating that it exerts its tissue-sparing effect by limiting lipid peroxidation in healthy tissues. The ability to override this protective mechanism by increasing iron levels adds compelling evidence to the idea that ferroptosis is a key driver of the FLASH effect.
Our findings reveal that intrinsic tissue iron levels dictate the extent of FLASH-RT protection through the modulation of lipid peroxidation and ferroptosis. This raises further questions about the types of cancer that would benefit from FLASH, particularly in iron rich tissues such as the liver or bone marrow. - Nuria Vilaplana Lopera, First author
‘Tissue-Specific Iron Levels Modulate Lipid Peroxidation and the FLASH Radiotherapy Effect’ was published in Cell Death & Disease on 2nd September 2025.