Tissue-specific iron levels modulate lipid peroxidation and the FLASH radiotherapy effect

Area of Science:

• Oncology
• Radiation Oncology
• Cell Biology

Background:

• Iron is essential for cell function, with cancer cells exhibiting higher iron dependency.
• Ferroptosis, an iron-dependent cell death, is a vulnerability in tumors.
• Radiation therapy (RT) can induce ferroptosis, but its mechanisms, especially with FLASH RT, require elucidation.

Purpose of the Study:

• To investigate the role of iron levels and lipid peroxidation in the protective effects of ultra-high dose rate FLASH RT on normal tissues.
• To determine if baseline iron differences between normal and tumor tissues mediate FLASH RT's differential effects.

Main Methods:

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

Main Results:

• FLASH RT significantly increased lipid peroxidation and ferroptosis in tumor cells but not in normal tissues.
• A high-iron diet reversed the protective effect of FLASH RT, leading to increased intestinal damage and lipid peroxidation in normal tissues.
• Baseline iron levels critically influence the protective outcomes of FLASH RT.

Conclusions:

• Differential iron dependency between normal and cancer cells underlies the protective effects of FLASH RT.
• Iron-driven lipid peroxidation is a key mechanism mediating FLASH RT's selective tumor toxicity and normal tissue sparing.
• Targeting iron metabolism could enhance the efficacy of FLASH RT.