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Abstract
Iron is vital to living cells, playing a key role in cellular respiration, DNA synthesis, and various metabolic functions. Importantly, cancer cells have a higher dependency on iron compared to normal cells to support their rapid growth and survival. Due to this fact, tumors are more vulnerable to ferroptosis, an iron-dependent form of regulated cell death. Radiation therapy (RT), a standard treatment for many cancer patients, is known to induce ferroptosis. Ultra-high dose rate FLASH RT offers an improved therapeutic window by minimizing damage to normal tissues while preserving tumor control. However, the precise biological mechanisms behind the protective effects of FLASH RT on normal tissues remain unclear. In this study, we propose that variations in lipid peroxidation and ferroptosis, driven by intrinsic differences in iron levels between normal and cancerous tissues, contribute to this effect. Our findings show that FLASH RT increases lipid peroxidation and induces ferroptosis in tumor cells but does not significantly elevate lipid peroxidation and ferroptosis in normal tissues compared to conventional RT. To determine whether raising iron levels in normal tissues could abrogate the protective effects of FLASH, mice were fed a high-iron diet before RT. A high-iron diet before and after RT reversed the protective effect of FLASH, resulting in increased intestinal damage and lipid peroxidation. This suggests that baseline iron levels and iron-driven lipid peroxidation are critical factors in mediating the protective outcomes of FLASH RT. Overall, our study sheds light on the role of iron in modulating RT responses and provides new mechanistic insights into how FLASH RT influences normal and cancerous tissues.

Affiliations

Nuria Vilaplana-Lopera # 1, Jiyoung Kim # 1, Gilyeong Nam 2, Iain D C Tullis 1, Salome Paillas 1, Jia-Ling Ruan 1, Pei Ju Lee 1 3, Yanyan Jiang 1, Sohee Park 4, Tianxu Hou 1, Ayesha Nasir 1, Eve Charlesworth 1, Ellie Walker 1, Ammar Abu-Halawa 1, Mark A Hill 1, Changhoon Choi 4, Ik Jae Lee 2, Youngtae Jeong 5, Samira Lakhal-Littleton 6, Chee Kin Then 7 8, Shing-Chuan Shen 3, Amato J Giaccia 1, Kristoffer Petersson 1, Eui Jung Moon 9
1Department of Oncology, University of Oxford, Oxford, UK.
2Department of Radiation Oncology, Severance Hospital, Yonsei University Medical School, Seoul, Republic of Korea.
3Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
4Department of Radiation Oncology, Samsung Medical Center, Seoul, Republic of Korea.
5Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu, Republic of Korea.
6Department of Physiology, Anatomy & Genetics, University of Oxford, Oxford, UK.
7Department of Radiation Oncology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan, ROC.
8Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC.
9Department of Oncology, University of Oxford, Oxford, UK. ejung.moon@oncology.ox.ac.uk.
#Contributed equally.