Dapagliflozin Mitigates Gamma Radiation-Induced Lung Injury in Rats Through Downregulation of Ferroptosis and Endoplasmic Reticulum Stress.

PURPOSE: This study was conducted to investigate the pharmacological effects and underlying mechanisms of dapagliflozin (DAPA) against a gamma radiation-induced lung injury model in rats, specifically on ferroptosis and endoplasmic reticulum stress (ERS) pathways.

METHODS

Four groups of rats were used. Group I served as the normal control. Group II rats received DAPA (10 mg/kg/d, p.o.) via orogastric gavage for 10 consecutive days. Group III served as a positive control group; rats were exposed to a single dose of whole-body gamma radiation (8 Gy) to induce lung injury. Group IV rats received DAPA (10 mg/kg/d, p.o.) for 10 consecutive days and were exposed to a single dose of whole-body gamma radiation (8 Gy) on day 5 of the experiment.

MAIN FINDINGS: Compared to control rats, DAPA significantly reduced radiation-induced lung injury (RILI), as demonstrated by biochemical and histological indicators. DAPA significantly mitigated the oxidative stress state induced by gamma radiation by increasing GSH levels and reducing MDA/ROS content in lung tissues. Moreover, DAPA significantly mitigated ferroptosis and ERS, as confirmed by the upregulation of GPX4 and downregulation of GRP78, CHOP, and ATF4, besides the fibrogenic marker α-SMA. Additionally, the above biochemical findings are concurrent with the histopathological results. Lung injury induced by gamma radiation was significantly improved by DAPA treatment.

CONCLUSION

These findings indicate that dapagliflozin exerts a radioprotective effect by alleviating gamma radiation-induced lung injury by regulating ferroptosis and ERS. These outcomes suggest that DAPA could be of value in the management of RILI.