Differential impact of FLASH and conventional radiotherapy on a pivotal metabolic organ: White Adipose Tissue

Scabia, G.; Furini, G.; Usai, A.; Asero, G.; Guerra, E.; Mota da Silva, E.; Kusmic, C.; Cavalieri, A.; Del Sarto, D.; Costa, M.; Wabitsch, M.; Rossi, F.; Di Pietro, R.; Lattanzio, S.; Luca, T.; Pezzino, S.; Castorina, S.; Cusano, R.; Capaccioli, S.; Gonnelli, A.; Paiar, F.; Di Martino, F.; Cinti, S.; Maffei, M.

doi:10.64898/2026.03.30.715260

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bioRxiv · 10.64898/2026.03.30.715260

Differential impact of FLASH and conventional radiotherapy on a pivotal metabolic organ: White Adipose Tissue

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Abstract

BACKGROUNDSubcutaneous white adipose tissue (scWAT), a key metabolic and endocrine organ, is inevitably exposed during radiotherapy (RT). While RT is a cornerstone of cancer treatment, its efficacy is limited by toxicity to surrounding healthy tissues. Ultra-high dose rate (FLASH) RT has emerged as a promising modality capable of preserving tumor control while reducing normal tissue damage - the so-called FLASH effect. Clinical evidence indicates that childhood exposure to conventional (CONV) RT is associated with long-term dysmetabolism and WAT dysfunction. However, the impact of FLASH-RT on WAT has not been investigated. AIMTo compare the effects of FLASH- and CONV-RT on adipocyte function and scWAT homeostasis, and to identify molecular and structural changes associated with each modality. METHODSWe evaluated the effects of FLASH- and CONV-RT on adipocytes and scWAT using a dedicated linear accelerator capable of delivering both modalities. Experiments were performed in the human SGBS preadipocyte/adipocyte cell line and in a mouse model subjected to proximal hind limb irradiation, with analyses conducted 70 days post-exposure. RESULTSRT impaired adipogenic differentiation in a dose-dependent manner, with a relative sparing effect of FLASH at 4-8 Gy. Mature adipocytes exhibited radioresistance, with protection by FLASH at 8 Gy. In vivo, both regimens reduced fat mass without affecting body weight, with greater loss following CONV-RT. Transcriptomic profiling of scWAT revealed inflammatory and neurodegenerative signatures after CONV-RT, whereas FLASH-RT induced minimal transcriptional changes. Histological and ultrastructural analyses confirmed increased cellular damage, vacuolization, lipid spill-over, and reduced PLIN1 expression, predominantly in CONV-treated mice. CONCLUSIONSWAT homeostasis is sensitive to conventional RT, whereas FLASH-RT better preserves tissue structure and function, with implications for long-term metabolic health in cancer survivors.

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Scabia, G., Furini, G., Usai, A., Asero, G., Guerra, E., Mota da Silva, E., Kusmic, C., Cavalieri, A., Del Sarto, D., Costa, M., Wabitsch, M., Rossi, F., Di Pietro, R., Lattanzio, S., Luca, T., Pezzino, S., Castorina, S., Cusano, R., Capaccioli, S., Gonnelli, A., Paiar, F., Di Martino, F., Cinti, S., Maffei, M.. 2026-04-01. Differential impact of FLASH and conventional radiotherapy on a pivotal metabolic organ: White Adipose Tissue. https://doi.org/10.64898/2026.03.30.715260

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