Wakabayashi, K. | Search bioRxiv

bioRxiv2026

Reprogramming of Lipid Metabolism by FLASH Radiotherapy Selectively Protects Radiosensitive Normal Tissues

FLASH radiotherapy, delivered at ultra-high dose rates exceeding 100 Gy/s, spares normal tissues while maintaining tumor control, yet the molecular mechanisms underlying this differential response remain poorly understood. Here we employed spatial and bulk multi-omics to investigate lipid and protein remodeling in tongue tissue and Mouse oral carcinoma 2 (MOC2) tumors at two weeks post-irradiation with FLASH or conventional dose-rate (CONV) proton radiotherapy. Bulk lipidomics revealed that CONV irradiation induced marked triglyceride (TG) depletion in tongue tissue, whereas FLASH attenuated this depletion. Spatial lipidomics using MALDI-MSI demonstrated that this TG loss was spatially restricted to minor salivary glands, identifying these radiosensitive structures as focal points of radiation-induced lipid damage. Additionally, FLASH irradiation uniquely promoted increases in membrane phospholipids and their lysophospholipid intermediates, consistent with active phospholipid turnover rather than passive damage avoidance. Proteomics revealed divergent metabolic programs: CONV activated a destructive cascade characterized by Ces1d depletion, Acox1-mediated peroxisomal {beta}-oxidation, and Acot7-driven fatty acid overflow, collectively defining a lipid droplet collapse; whereas FLASH engaged a protective program featuring Mgll suppression, Apoe-mediated triglyceride redistribution, and Lypla2-mediated lysophospholipid clearance. We propose a lipid metabolic reprogramming hypothesis in which FLASH not only minimizes acute oxidative damage but actively reprograms lipid metabolism to preserve lipid droplet stores and promote membrane remodeling. These findings provide a putative molecular foundation for the FLASH effect and support published data on the protection of normal tissues.

cancer biology↗

bioRxiv2017

Analysis of ancient human mitochondrial DNA from Verteba Cave, Ukraine: insights into the origins and expansions of the Late Neolithic-Chalcolithic Cututeni-Tripolye Culture

BackgroundThe Eneolithic (~ 5,500 yrBP) site of Verteba Cave in Western Ukraine contains the largest collection of human skeletal remains associated with the archaeological Cucuteni-Tripolye Culture. Their subsistence economy is based largely on agro-pastoralism and had some of the largest and most dense settlement sites during the Middle Neolithic in all of Europe. To help understand the evolutionary history of the Tripolye people, we performed mtDNA analyses on ancient human remains excavated from several chambers within the cave.\n\nResultsBurials at Verteba Cave are largely commingled and secondary in nature. A total of 68 individual bone specimens were analyzed. Most of these specimens were found in association with well-defined Tripolye artifacts. We determined 28 mtDNA D-Loop (368 bp) sequences and defined 8 sequence types, belonging to haplogroups H, HV, W, K, and T. These results do not suggest continuity with local pre-Eneolithic peoples, but rather complete population replacement. We constructed maximum parsimonious networks from the data and generated population genetic statistics. Nucleotide diversity ({pi}) is low among all sequence types and our network analysis indicates highly similar mtDNA sequence types for samples in chamber G3. Using different sample sizes due to the uncertainly in number of individuals (11, 28, or 15), we found Tajimas D statistic to vary. When all sequence types are included (11 or 28), we do not find a trend for demographic expansion (negative but not significantly different from zero); however, when only samples from Site 7 (peak occupation) are included, we find a significantly negative value, indicative of demographic expansion.\n\nConclusionsOur results suggest individuals buried at Verteba Cave had overall low mtDNA diversity, most likely due to increased conflict among sedentary farmers and nomadic pastoralists to the East and North. Early Farmers tend to show demographic expansion. We find different signatures of demographic expansion for the Tripolye people that may be caused by existing population structure or the spatiotemporal nature of ancient data. Regardless, peoples of the Tripolye Culture are more closely related to early European farmers and lack genetic continuity with Mesolithic hunter-gatherers or pre-Eneolithic groups in Ukraine.

evolutionary biology↗