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Background <p>Radiotherapy (RT) for treating breast cancer can result in incidental dose deposition to the liver, leading to functional impairment. FLASH radiotherapy (FLASH-RT), delivered at ultra-high dose rates (UHDR), has demonstrated remarkable normal tissue sparing. We investigated the hepatoprotective effects and metabolic alterations associated with FLASH-RT and conventional radiotherapy (CONV-RT) in a preclinical breast cancer model.</p> Methods <p>Female BALB/c mice bearing syngeneic 4T1 breast tumors were randomized to receive a single 20&#xa0;Gy fraction of either FLASH-RT (625&#xa0;Gy/s) or CONV-RT (0.54&#xa0;Gy/s) using a 6&#xa0;MeV electron beam. Tumor kinetics and systemic toxicity were monitored for 14 days. Hepatic integrity was assessed via histology, immunohistochemistry, oxidative-stress markers, serum biochemical assays, and non-targeted UPLC-MS/MS metabolomics of liver tissue.</p> Results <p>Both modalities achieved isoeffective tumor growth delay. However, FLASH-RT induced only transient body-weight reduction followed by rapid recovery, and was associated with reduced hepatic injury markers compared with CONV-RT. Histopathological analysis revealed that FLASH-RT preserved hepatic architecture and attenuated early pro-fibrotic signaling, as reflected by reduced α-SMA and Nestin expression compared with CONV-RT. FLASH-treated mice exhibited significantly lower serum ALT/ALP levels and reduced oxidative stress (lower MDA levels and higher GSH-PX levels). Furthermore, FLASH-RT attenuated immune-mediated inflammation, as evidenced by diminished infiltration of CD8 + T cells and F4/80 + macrophages. Metabolomic profiling demonstrated that FLASH-RT preserved hepatic metabolic homeostasis, preventing the profound lipid and choline metabolism disruptions observed following CONV-RT.</p> Conclusions <p>FLASH-RT was associated with substantial hepatic sparing by preserving structural integrity, attenuating oxidative–inflammatory signaling, and maintaining metabolic stability. These findings suggest that FLASH-RT may help expand the therapeutic window by uncoupling antitumor efficacy from collateral hepatic toxicity.</p>

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FLASH radiotherapy preserves hepatic function and maintains metabolic homeostasis in a murine breast cancer model: an experimental preclinical study

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月19日

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  • Xingyu Lu,
  • Dehuan Xie,
  • Liang Cui,
  • Hang Shang,
  • Linghong Zhou

摘要

Background

Radiotherapy (RT) for treating breast cancer can result in incidental dose deposition to the liver, leading to functional impairment. FLASH radiotherapy (FLASH-RT), delivered at ultra-high dose rates (UHDR), has demonstrated remarkable normal tissue sparing. We investigated the hepatoprotective effects and metabolic alterations associated with FLASH-RT and conventional radiotherapy (CONV-RT) in a preclinical breast cancer model.

Methods

Female BALB/c mice bearing syngeneic 4T1 breast tumors were randomized to receive a single 20 Gy fraction of either FLASH-RT (625 Gy/s) or CONV-RT (0.54 Gy/s) using a 6 MeV electron beam. Tumor kinetics and systemic toxicity were monitored for 14 days. Hepatic integrity was assessed via histology, immunohistochemistry, oxidative-stress markers, serum biochemical assays, and non-targeted UPLC-MS/MS metabolomics of liver tissue.

Results

Both modalities achieved isoeffective tumor growth delay. However, FLASH-RT induced only transient body-weight reduction followed by rapid recovery, and was associated with reduced hepatic injury markers compared with CONV-RT. Histopathological analysis revealed that FLASH-RT preserved hepatic architecture and attenuated early pro-fibrotic signaling, as reflected by reduced α-SMA and Nestin expression compared with CONV-RT. FLASH-treated mice exhibited significantly lower serum ALT/ALP levels and reduced oxidative stress (lower MDA levels and higher GSH-PX levels). Furthermore, FLASH-RT attenuated immune-mediated inflammation, as evidenced by diminished infiltration of CD8 + T cells and F4/80 + macrophages. Metabolomic profiling demonstrated that FLASH-RT preserved hepatic metabolic homeostasis, preventing the profound lipid and choline metabolism disruptions observed following CONV-RT.

Conclusions

FLASH-RT was associated with substantial hepatic sparing by preserving structural integrity, attenuating oxidative–inflammatory signaling, and maintaining metabolic stability. These findings suggest that FLASH-RT may help expand the therapeutic window by uncoupling antitumor efficacy from collateral hepatic toxicity.