Objective To explore the protective effect of Gingerenone A (GA) on hypoxic-ischemic brain damage (HIBD) in neonatal rats and its influence on the nuclear factor E2-related factor 2 (Nrf2)/glutathione peroxidase 4 (GPX4) pathway.Methods 7-day-old SD neonatal rats were divided into sham group, HIBD group, HIBD+10GA group, HIBD+20GA group, HIBD+40GA group and GPX4-IN-3 group. The HIBD model was established by referring to the Rice-Vannucci method. Rats in the sham group were not modeled, and rats in the other groups were HIBD model rats. After successful modeling, rats in the HIBD+10GA group, HIBD+20GA group and HIBD+40GA group were respectively given GA solutions with gavage doses of 10, 20 and 40 mg/kg. Rats in the GPX4-IN-3 group were simultaneously given an intragastric dose of 40 mg/kg of GA and 15 mg/kg of GPX4-IN-3 (a GPX4 inhibitor), while rats in sham group and HIBD group were given an equal amount of a mixture of normal saline containing 1% DMSO by gavage, once a day for 3 consecutive days. After administration, the neurobehavior of rats was evaluated through the forelimb suspension test and the open field test. Brain tissue injury was evaluated by TTC staining, HE staining and Nissl staining, and neuronal cell injury in brain tissue was detected by immunofluorescence staining. The levels of oxidative stress indicators (SOD and MDA) and the content of Fe2+ in brain tissue were detected by reagent kits, and ROS was detected by DHE probes. The protein expressions of IL-1β, IL-6, TNF-α, Nrf2, GPX4 and SLC7A11 were detected by Western blot. Results The morphology and structure of nerve cells in the sham operation group of rats were both clear and intact. In the HIBD group, the nerve cells of rats were disordered in arrangement, with vacuolation, swelling and necrosis of cells, and abnormal morphology and quantity of Nistellae bodies. In the HIBD+10GA group, the HIBD+20GA group and the HIBD+40GA group, the arrangement of nerve cells in rats tended to be normal, vacuolated and necrotic cells gradually decreased, and the number of normal Nistellae bodies increased. The abnormal conditions of the morphology and quantity of nerve cells and Nisco bodies in the GPX4-IN-3 group of rats were similar to those in HIBD rats. Compared with sham group, the suspension time and movement distance of the forelimbs of rats in HIBD group were both decreased (P＜0.05), and the rest time was increased (P＜0.05). The cerebral infarction volume, the proportion of Fluoro-Jade C positive cells, the contents of MDA and Fe2+, and the relative level of ROS were all increased (P＜0.05), and the protein expression levels of IL-1β, IL-6 and TNF-α were all increased (P＜0.05). The levels of SOD and the protein expression levels of Nrf2, GPX4, and SLC7A11 were all decreased (P＜0.05). Compared with HIBD group, the suspension time and movement distance of the forelimbs of rats in HIBD+10GA group, HIBD+20GA group and HIBD+40GA group were both increased (P＜0.05), and the rest time was decreased (P＜0.05). The cerebral infarction volume, the proportion of Fluoro-Jade C positive cells, the contents of MDA and Fe2+, and the relative level of ROS were all decreased (P＜0.05), and the protein expression levels of IL-1β, IL-6 and TNF-α were all decreased (P＜0.05). The levels of SOD and the protein expression levels of Nrf2, GPX4, and SLC7A11 were all increased (P＜0.05). Compared with HIBD+40GA group, the suspension time and movement distance of the forelimbs of rats in GPX4-IN-3 group were both decreased (P＜0.05), and the rest time was increased (P＜0.05). The cerebral infarction volume, the proportion of Fluoro-Jade C positive cells, the contents of MDA and Fe2+, and the relative level of ROS were all increased (P＜0.05), and the protein expression levels of IL-1β, IL-6 and TNF-α were all increased (P＜0.05). The levels of SOD and the protein expression levels of Nrf2, GPX4, and SLC7A11 were all decreased (P＜0.05). Conclusion GA can effectively alleviate HIBD in neonatal rats, and the mechanism may be related to the inhibition of inflammation, oxidative stress response and ferroptosis, as well as the activation of the Nrf2/GPX4 pathway