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Background: Subcutaneous white adipose tissue (scWAT) is a major energy reservoir and an active endocrine organ. Owing to its widespread distribution, scWAT is inevitably exposed during conventional (CONV) radiotherapy (RT). Although RT remains a cornerstone of cancer treatment, its therapeutic efficacy is limited by toxicity to surrounding healthy tissues. Ultra-high dose rate (FLASH) RT has recently emerged as a promising modality capable of preserving tumor control while markedly reducing normal tissue damage, the so-called FLASH effect. Clinical evidence indicates that individuals exposed to RT during childhood frequently develop lipodystrophy and metabolic dysfunction later in life; however, the underlying mechanisms remain poorly understood. Notably, the effects of FLASH RT on WAT have not yet been investigated.
Aim: To examine and compare the effects of FLASH and CONV RT on adipocytes and subcutaneous white adipose tissue.
Materials and Methods: In vitro studies were performed using the human SGBS preadipocyte/adipocyte cell line, while in vivo experiments were conducted in male C57BL/6 mice. Confluent undifferentiated SGBS cells were irradiated and subsequently induced to differentiate or irradiated at terminal differentiation. Irradiations were delivered using a linear accelerator capable of administering both CONV and FLASH RT at doses of 4, 8, and 16 Gy. Triglyceride accumulation and adipocyte function were assessed by Oil Red O staining and gene expression analyses.
For in vivo studies, mice received a single 35 Gy irradiation to the proximal hind limb and were sacrificed 70 days post-irradiation. scWAT from the irradiated region was analyzed using histological approaches (H&E and Sirius Red staining, immunohistochemistry), light and transmission electron microscopy, and bulk RNA sequencing.
Results: RT impaired adipogenic differentiation in a dose-dependent manner, with a clear sparing effect of FLASH irradiation at 4–8 Gy. Mature adipocytes displayed relative radioresistance, with a significant protective effect of FLASH observed at 8 Gy. In vivo, both irradiation regimens induced a reduction in scWAT mass despite comparable total body weights, with fat loss being more pronounced following CONV-RT. Transcriptomic profiling of irradiated scWAT revealed robust activation of inflammatory and neurodegenerative pathways after CONV-RT, whereas FLASH-RT induced minimal to no transcriptional alterations. Consistently, histological and ultrastructural analyses showed marked cellular damage in CONV-RT treated mice, including increased vacuolization, lipid spill-over, and reduced PLIN1 immunoreactivity. These alterations were markedly attenuated or absent following FLASH-RT.
Conclusions: These findings demonstrate that WAT homeostasis is highly sensitive to CONV-RT, whereas FLASH-RT more effectively preserves its structure and function. This differential response has important implications for the long-term metabolic health of cancer survivors. Moreover, we provide novel mechanistic insights into RT-induced WAT dysfunction and identify new trajectories for understanding and potentially mitigating RT-related metabolic sequelae.
