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

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 f...

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Vydáno v:Cell death & disease Ročník 16; číslo 1; s. 668 - 14
Hlavní autoři: Vilaplana-Lopera, Nuria, Kim, Jiyoung, Nam, Gilyeong, Tullis, Iain D. C., Paillas, Salome, Ruan, Jia-Ling, Lee, Pei Ju, Jiang, Yanyan, Park, Sohee, Hou, Tianxu, Nasir, Ayesha, Charlesworth, Eve, Walker, Ellie, Abu-Halawa, Ammar, Hill, Mark A., Choi, Changhoon, Lee, Ik Jae, Jeong, Youngtae, Lakhal-Littleton, Samira, Then, Chee Kin, Shen, Shing-Chuan, Giaccia, Amato J., Petersson, Kristoffer, Moon, Eui Jung
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 02.09.2025
Springer Nature B.V
Nature Publishing Group
Témata:
13/51
13/89
631/67/327
64/60
692/308/2778
96/106
Animals
Antibiotics
Antibodies
Biochemistry
Biomedical and Life Sciences
Cancer therapies
Cell Biology
Cell Culture
Cell death
Cell Line, Tumor
Diet
DNA biosynthesis
Dosimetry
Experiments
Ferroptosis
Ferroptosis - radiation effects
Humans
Immunology
Iron
Iron - metabolism
Life Sciences
Lipid peroxidation
Lipid Peroxidation - radiation effects
Lipids
Mice
Mice, Inbred C57BL
Neoplasms - metabolism
Neoplasms - pathology
Neoplasms - radiotherapy
Organ Specificity
Radiation therapy
Radiotherapy - methods
Tumor cells
Tumors
United Kingdom > UK
Japan
Germany
ISSN:2041-4889, 2041-4889
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Shrnutí: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.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-025-07988-0