2913 - Effects of FLASH Irradiation on Liver Metabolomics in Mice Subjected to Partial-Liver Irradiation

D. Xie¹, W. Feng², X. Lu³, A. Q. Chen⁴, P. Tan¹, Y. Lei¹, Y. Liu¹, C. Chen², Q. Zhang², S. Hu², H. Ye², M. Liu², X. Lin², C. Ren¹, and S. Du¹; ¹Guangdong Provincial Peoples Hospital, Guangzhou, Guangdong, China, ²Guangdong Provincial Peoples Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong, China, ³Southern Medical University, Guangzhou, China, ⁴Department of Radiation Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong, China

Purpose/Objective(s): Ultrahigh dose-rate irradiation (FLASH) has been shown to effectively control tumors while reducing damage to normal tissues. However, the specific effects of FLASH on liver tissue and its underlying mechanisms are not yet fully understood. The objective of this study is to evaluate the occurrence of radiation-induced liver disease (RILD) after treatment with either FLASH or conventional (CONV) irradiation. Additionally, the study aims to investigate the impact of FLASH on liver metabolomics. Materials/

Methods: Groups of female BALB/c mice (n=5 per group) were exposed to 20 Gy of FLASH or CONV irradiation using a PN-FLASH Photon FLASH Radiotherapy Experimental System in Southern Medical University (Guangzhou, China). At 4 days or 20 days post treatment, all animals were euthanized and both plasma and liver tissues obtained. Serum biochemistry, histological analyses and a semi-quantitative untargeted metabolites/lipid profiling using LC-MS platforms was performed.
Results: Following a 20-day observation period of mice exposed to 20 Gy of irradiation, the FLASH group exhibited a more rapid recovery of body weight compared to the CONV group. Histological analysis revealed that FLASH treatment resulted in less liver damage compared to CONV treatment. Serum measurements indicated that levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were elevated at 20 days after CONV treatment, while triglyceride (TG) and cholesterol (CHO) levels were elevated at 4 days but reduced at 20 days after CONV treatment. In contrast, these levels remained unchanged after FLASH treatment. Furthermore, a total of 258 candidate liver metabolites were screened and identified. Gene Set Enrichment Analysis (GSEA) demonstrated significant differences in pathways related to unsaturated fatty acid synthesis, sphingolipid signaling, and other fatty acid metabolism between the FLASH and CONV groups. Notably, differentially expressed metabolites such as all-trans-Retinoic acid, eicosatetraenoic acid, and docosatrienoic acid, which are associated with lipid metabolism, were found to be decreased in the FLASH group compared to the CONV group. A circular plot of KEGG pathways illustrated that the majority of the identified metabolites were linked to fatty acid metabolism.
Conclusion: Compared to CONV, FLASH resulted in reduced liver damage. Liver profiling of specific metabolites associated with fatty acid metabolism can serve as a distinguishing factor between RILD caused by FLASH and CONV treatments.