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

Authors

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

Published in

Radiation oncology (London, England). Jun 19, 2026. Epub Jun 19, 2026.

Abstract

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.
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.
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.
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.

PMID:
42321761
Bibliographic data and abstract were imported from PubMed on 20 Jun 2026.

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