Ionizing Radiation Induces Ferroptosis In Splenic Lymphocytes Of Mice

Backgrounds: It remains unclear whether radiation-induced haemorrhage in the spleen causes iron accumulation, and subsequently, ferroptosis in splenic lymphocytes. In this study, we investigated the occurrence of ferroptosis in splenic lymphocytes of gamma-irradiated mice. Materials and Methods: Mice were subjected to gamma radiation from a Cs-137 source. Iron, Ferroportin 1, and iron regulatory protein (IRP) levels in the spleen, and serum iron and hepcidin levels in the blood were measured to study the change in iron metabolism of the irradiated spleen. After Ferrostatin 1/LDN193189 was intraperitoneally injected into mice post-irradiation, the viability of splenic lymphocytes and the splenic index were evaluated to investigate the mechanism of damage induction in splenic lymphocytes. The survival rate of mice was evaluated to identify the radiation mitigator based on the inhibition of ferroptosis. Results: Iron accumulation (up to 0.62 g/g) observed in the spleen of irradiated mice was due to haemorrhage-based haemosiderin. The iron accumulation triggered the IRP-ferroportin 1 axis to increase the level of serum iron to 121.65 mmol/l. LDN193189 was used to demonstrate that the iron accumulation decreased the viability of splenic lymphocytes in irradiated mice, which was subsequently demonstrated to attribute to ferroptosis with the use of Ferrostatin 1 and through detection of ferroptosis-related parameters. The survival rate of irradiated mice was improved upon Ferrostatin-1 (60% with a duration of 120 days) or LDN193189 (40% for the same duration) treatment. Conclusion: Radiation-induced haemorrhage causes ferroptosis in splenic lymphocytes, and anti-ferroptosis is a potential strategy to alleviate immune damage in hematopoietic acute radiation sickness.