Tissue-Specific Iron Levels Modulate Lipid Peroxidation and the FLASH Radiotherapy Effect

Area of Science:

• Oncology
• Radiation Oncology
• Cellular Biology

Background:

• Iron is essential for cell function, but cancer cells exhibit higher iron dependency for growth.
• Ferroptosis, an iron-dependent cell death, is a vulnerability in tumors and can be induced by radiation therapy (RT).
• Ultra-high dose rate FLASH RT shows promise for improved cancer treatment by sparing normal tissues.

Purpose of the Study:

• To investigate the role of iron levels and ferroptosis in the protective mechanisms of FLASH RT on normal tissues.
• To elucidate the differential impact of FLASH RT on lipid peroxidation and ferroptosis in tumor versus normal cells.
• To determine if manipulating iron levels in normal tissues affects FLASH RT's protective outcomes.

Main Methods:

• Comparison of lipid peroxidation and ferroptosis induction in tumor and normal tissues after conventional RT and FLASH RT.
• Administration of a high-iron diet to mice before and after FLASH RT to assess its impact on normal tissue damage.
• Assessment of intestinal damage and lipid peroxidation levels in response to iron-enriched diets and RT.

Main Results:

• FLASH RT significantly increased lipid peroxidation and induced ferroptosis in tumor cells.
• Normal tissues showed no significant increase in lipid peroxidation or ferroptosis with FLASH RT compared to conventional RT.
• A high-iron diet reversed the protective effects of FLASH RT, leading to increased intestinal damage and lipid peroxidation in normal tissues.

Conclusions:

• Baseline iron levels critically influence the protective effects of FLASH RT on normal tissues.
• Iron-driven lipid peroxidation is a key mediator of FLASH RT's differential response between normal and cancerous tissues.
• Targeting iron metabolism may enhance the therapeutic efficacy and safety of FLASH RT in cancer treatment.