Selective lipid Metabolic remodelling in radiosensitive normal tissues after FLASH radiotherapy.

Authors

Shuhei Aramaki, Maxime Dubail, Mathieu Sertorio, Md Muedur Rahman, Mst Sayela Afroz, Chi Zhang, Liang Tang, Kohei Wakabayashi, Kenta Konishi, Tomoaki Kahyo, Gael Boivin, Marta Vilalta, Ricky A Sharma, Katsumasa Nakamura, Mitsutoshi Setou

Published in

Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. Pages 111825. Oct 14, 2026. Epub Oct 14, 2026.

Abstract

FLASH radiotherapy, delivered at ultra-high dose rates, spares normal tissues while maintaining tumor control, but the molecular basis of this differential response remains poorly defined, particularly at timepoints relevant to tissue repair. We investigated whether lipid metabolism contributes to the FLASH effect in head and neck cancer.
MOC2 tumor-bearing mice received a single 10 Gy fraction of conventional (CONV) or ultra-high dose-rate FLASH protons, with non-irradiated controls (CTRL). Tongue and contralateral tumors were collected two weeks later and analyzed by bulk lipidomics, spatial lipidomics and proteomics. After biochemical filtering, 1,547 lipid species across 37 classes were quantified.
At two weeks, CONV irradiation was associated with a triglyceride-catabolic, oxidative-stress signature in tongue tissue, marked by loss of the lipid-droplet hydrolase Ces1d alongside induction of the peroxisomal β-oxidation enzyme Acox1. FLASH irradiation was instead associated with a distinct lipid-remodelling signature: suppression of Mgll, induction of Apoe, membrane phospholipid remodelling (increased phosphatidylcholine and phosphatidylethanolamine), and Lypla2 upregulation. Spatial lipidomics provided illustrative spatial context consistent with concentration of these changes in minor salivary gland acini. Tumor tissue showed no comparable modality-specific divergence.
These correlative multi-omics data indicate that FLASH is associated with remodelling of lipid metabolism in radiosensitive normal tissue, beyond a simple reduction of acute oxidative damage. We propose a Lipid Metabolic Remodelling Hypothesis for testing: the remodelling of lipid metabolism observed after FLASH may contribute to normal-tissue sparing rather than representing solely a downstream consequence of reduced acute oxidative damage. This model complements existing physicochemical models and offers a basis for radioprotection strategies in head and neck radiotherapy.

PMID:
42874779
Bibliographic data and abstract were imported from PubMed on 15 Oct 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.