Abstract： Objective:To investigate the effects of carbamylated erythropoietin（C-EPO）on the nuclear factor E2-related factor 2（NRF2）/glutathione peroxidase 4（GPX4）pathway and ferroptosis in the lung tissue of rats with traumatic brain injury（TBI）combined with seawater drowning（SWD）.Methods:A total of 48 Sprague-Dawley（SD）rats were randomly divided into four groups，according to random number table method，i.e.，sham group，TBI+SWD group，C-EPO group，and C-EPO+ML385 group，with 18 rats in each group（each group has six spare rats）. The TBI+SWD rat model was established using the controlled cortical impact（CCI）method followed by seawater instillation（3 ml/kg）through the trachea. C-EPO was administered by intraperitoneal injection at a dose of 50 μg/kg every 24 hours；and ML385，the Nrf2 inhibitor，was administered at a dose of 30 mg/kg once daily. The neurological function scores and lung tissue water contents were assessed；lung morphology was observed by HE staining；iron deposition in lung tissue was evaluated by Prussian blue staining；and the contents of iron，malondialdehyde（MDA），and glutathione（GSH）and GPX4 activity in lung tissue were measured by spectrophotometric assay. The expression levels of Nrf2 mRNA and GPX4 mRNA in the lung tissue were assessed by quantitative PCR（qPCR）.Results:The differences in neurological function scores at 24 hours post-injury were statistically significant among the four groups（ F=21.30， P<0.001），with the TBI+SWD group and the C-EPO+ML385 group showing lower scores compared with the sham group and the C-EPO group（ P<0.05）. Lung tissue water contents at 24 hours post-injury also exhibited significant differences among the four groups（ F=31.21， P<0.001），with the TBI+SWD group，the C-EPO group，and the C-EPO+ML385 group displaying higher water contents than the sham group，and the TBI+SWD group and the C-EPO+ML385 group displaying higher water contents than the C-EPO group（ P<0.05）. Iron deposition in the lung tissue at 24 hours post-injury showed significant differences among the four groups（ F=872.1， P<0.001），with the TBI+SWD group showing higher iron deposition in the lung tissue compared with the sham group and the C-EPO group（ P<0.05）. The differences of the contents of iron，MDA，and GSH and GPX4 activity at 24 hours post-injury were statistically significant in the four groups（ F=748.18，453.24，121.37，and 1 042.31；all P<0.001）. The contents of iron and MDA in the TBI+SWD group and the C-EPO+ML385 group were all higher than those in the sham group and the C=EPO group，while the contents of GSH and GPX4 activity were all lower than those in the sham group and the C=EPO group（ P<0.05）. The expression levels of NRF2 mRNA and GPX4 mRNA in the lung tissue at 24 hours post-injury were significantly different among the groups（ F=96.24 and 432.49；all P<0.001）. The expression levels of NRF2 mRNA and GPX4 mRNA in the lung tissue of the TBI+SWD group and the C-EPO+ML385 group were all lower than those in the sham group and the C-EPO group（ P<0.05）. Conclusion:C-EPO may inhibit ferroptosis occurrence in the lung tissue of the TBI+SWD rats by regulating the Nrf2/GPX4 signaling axis.