Biology subjects

Castorina, S.

Publications and source records attributed to Castorina, S..

3 recordsLinked to original sources

bioRxiv2026

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

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.

physiology↗

bioRxiv2025

Role of Hypertrophic Adipocytes, Collagen VI and CD38 in Fat Fibrosis of Patients with Obesity

Fat fibrosis correlates to metabolic consequences in patients with obesity, and is due to three types of collagen: I and III (fibrillar) and VI (non-fibrillar). In this sudy the extent of fibrosis in obese patients (n 50) was significant only in visceral parenchymal fat (4.7% vs 2.5% in controls (n 15) P<0.0001) and not in subcutaneous fat. Electron microscopy, in vivo and in vitro data, suggested that obese adipocytes are responsible for fibrillar collagen (I and III) production. COL6 (gene producing the non fibrillar form) resulted less expressed. In line, patients with COL6 mutations, showed increased fibrotic tissue even in subcutaneous fat: about 6.5 times vs controls in the patient with the severe form (Ullrich) and 2.8 times in two patients with the milder form (Bethlem). Approximately 15% of obese adipocytes were dead (perilipin1 negative), and consequent infiltrating macrophages showed hyperexpression of CD38, an ectoenzyme implicated in systemic fibrosis. Correlations with gene expression confirmed the importance also of myofibroblasts and the extracellular matrix peptidase D. All together our data support a role for obese adipocytes in the fibrillar collagen production and evidentiate collagen VI and CD38 as new molecular determinants, reinforcing the idea of a multi-factorial origin of fat fibrosis.

cell biology↗

bioRxiv2025

Localized FLASH Radiotherapy Reduces Long-Term Skin and Muscle Damage While Preserving Systemic Homeostasis

Radiotherapy (RT) is a cornerstone treatment for nearly 50% of cancer patients, but its curative potential and safe dosing are constrained by cumulative toxicity to surrounding healthy tissues. Delivering RT at ultra-high dose rates (FLASH-RT) represents a transformative strategy, as it appears to maintain tumor control, while sparing normal tissue. Melanoma is among the most radioresistant tumors, and skin and muscle are invariably exposed during RT, also in case of deep seated tumors. Here, we compared electron FLASH-RT and conventional RT (CONV-RT) in melanoma-bearing and naive mice assessing tumor control, tissue integrity, and systemic homeostasis over the medium to long term. Both modalities achieved comparable tumor suppression. However, CONV-RT induced persistent skin damage, dermal fibrosis, muscle dysfunction and systemic inflammatory-metabolic alterations, while FLASH-RT largely spared normal tissue and systemic balance. Bulk RNA sequencing revealed striking differences: FLASH induced minimal transcriptional disruption in skin and muscle, whereas CONV-RT triggered thousands of differentially expressed genes, including massive activation of fibrosis, inflammation, cell death-related pathways in skin, and broad dysregulation of genes linked to muscle function, remodeling and the unfolded protein response. Histological and ultrastructural analyses corroborated the findings, showing reduced immune infiltration in the skin and preserved tissue architecture both in skin and muscle following FLASH. In conclusion our study not only confirms the protective nature of FLASH but also provides novel mechanistic insights into the cascade linking local injury to systemic dysfunction under CONV-RT, reinforcing the translational potential of FLASH to expand the therapeutic window of radiotherapy. One Sentence SummaryComparative analysis of FLASH and conventional radiotherapy in a murine model of melanoma and naive mice - Therapeutical efficacy, local and systemic effects.

physiology↗