Sep 28

PQA 03 - Digital Health Innovation and Informatics, Patient Safety & Quality, and Radiation and Cancer Biology

2474 - Molecular Mechanism of Amelioration of Ionising Radiation-Induced Myocardial Injury by Deferoxamine

10:45am - 12:00pm ET

Poster Hall - Exhibit Hall A

Screen: 10

Presenter(s)

Yikun He, MD - State Key Laboratory of Molecular Oncology and Department of Radiation Oncology, National Cancer Center / National Clinical Research Center for Cancer / Cancer Hospital, Beijing,

Y. He, X. Chen, W. Xiang, R. Xu, X. 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):

Radiation-induced myocardial injury is a serious complication of thoracic radiotherapy, closely linked to mitochondrial oxidative stress and iron dysregulation. Deferoxamine(DFO), a natural iron chelator with antioxidant properties, remains unexplored in this context. This study investigates whether DFO attenuates radiation-induced myocardial damage and elucidates its mechanism involving the LCN2-siderophore axis and ferroptosis inhibition.

Materials/Methods:

Wild-type(WT)mice and LCN2 knockout (LKO) mice were subjected to cardiac irradiation to establish RIMI. Cardiac function, histopathology, fibrosis, iron deposition, and ferroptosis-related markers were assessed with or without DFO treatment. Ferroptosis-associated proteins were analyzed by immunoblotting. To define cell-type–specific mechanisms,scRNA-seq was performed on cardiac tissues to characterize LCN2 expression patterns and iron-related signaling pathways.

Results:

Compared with WT mice,LKO mice exhibited attenuated radiation-induced cardiac dysfunction, fibrosis, and iron accumulation, with increased GPX4/FTH1 and reduced ACSL4 expression, indicating suppressed ferroptosis. The cardioprotective effects of DFO were significantly diminished in LKO mice, suggesting partial dependence on an intact LCN2 pathway. scRNA-seq revealed radiation-induced upregulation of LCN2 and iron metabolism genes primarily in cardiomyocytes and fibroblasts, accompanied by activation of ferroptosis and mitochondrial stress pathways. These changes were selectively attenuated by DFO, particularly in LCN2-high cell populations.

Conclusion:

LCN2 plays a critical role in radiation-induced myocardial injury by regulating iron uptake and ferroptosis. The cardioprotective effects of DFO are partially dependent on the LCN2–iron transport axis. Single-cell transcriptomic analyses further support a cell type–specific role of LCN2-mediated iron dysregulation in RIMI, highlighting this pathway as a potential target for mitigating radiation-associated cardiac toxicity.