1262 - Chorismic Acid and Radiation-Induced Intestinal Injury through Bdh2-Dependent Antioxidant and Metabolic Reprogramming
Presenter(s)
W. Xiang, X. Chen, X. Xu, Y. He, R. Xu, and M. Deng; State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Purpose/Objective(s):
To investigate the radioprotective effects of Chorismic acid (CA) against ionizing radiation–induced intestinal injury and to systematically elucidate the underlying Bdh2-dependent mechanisms through integrated multi-omics and genetic approaches.
Materials/Methods:
Murine models of radiation-induced intestinal injury and irradiated NCM460 intestinal epithelial cells were established. Histological, molecular, and functional assays were used to evaluate the effects of CA on intestinal damage, fibrosis, oxidative stress, inflammation, and apoptosis. Integrated multi-omics analyses, single-cell RNA sequencing, and flow cytometry were employed to identify key signaling pathways, metabolic alterations, and principal target cell populations. Genetic dependency was further validated using intestinal epithelial cell–specific Bdh2?IEC mice.
Results:
CA significantly attenuated radiation-induced intestinal injury and fibrosis, accompanied by suppression of the TGF-ß/CTGF signaling axis. CA enhanced antioxidant capacity, as evidenced by increased T-AOC, GSH-PX, and T-SOD activities and reduced MDA levels, indicating marked alleviation of oxidative stress. Transcriptomic analysis revealed that CA broadly suppressed radiation-induced inflammatory, apoptotic, and stress-related gene programs, with significant downregulation of pro-apoptotic genes including Sept4 and Gsdme. Untargeted metabolomic profiling further demonstrated that CA markedly reshaped linoleic acid and arachidonic acid metabolic pathways, reducing multiple pro-inflammatory lipid mediator–associated metabolites, consistent with transcriptomic evidence of lipid metabolic reprogramming. Single-cell RNA sequencing showed that CA primarily acted on intestinal epithelial and myeloid cell subsets, reversing radiation-induced pro-inflammatory transcriptional reprogramming and promoting epithelial homeostasis. Flow cytometric analysis confirmed that CA reduced radiation-induced infiltration of pro-inflammatory myeloid cells and decreased intestinal epithelial apoptosis. In intestinal epithelial cell–specific Bdh2?IEC mice, CA failed to ameliorate radiation-induced transcriptomic reprogramming, lipid metabolic dysregulation, or abnormal immune cell infiltration, indicating that its radioprotective effects are dependent on Bdh2.
Conclusion:
CA mitigates ionizing radiation–induced intestinal injury through Bdh2-dependent antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. Integrated multi-omics, single-cell, and genetic evidence establishes the Bdh2–CA axis as a key regulator of intestinal radiation responses.