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[Display omitted] • TBI causes oxidative stress and neuroinflammation in brain tissue, which in turn causes ferroptosis. • DFO can reduce oxidative stress and iron death levels after TBI. • GSNO reduces TBI-induced neurodegeneration and aids in functional recovery. • DFO can reduce NF-kb pathway expression after TBI, which in turn reduces pyroptosis and attenuates neuroinflammation. Traumatic brain injury (TBI) is an important reason of neurological damage and has high morbidity and mortality rates. The secondary damage caused by TBI leads to a poor clinical prognosis. According to the literature, TBI leads to ferrous iron aggregation at the site of trauma and may be a key factor in secondary injury. Deferoxamine (DFO), which is an iron chelator, has been shown to inhibit neuron degeneration; however, the role of DFO in TBI is unclear. The purpose of this study was to explore whether DFO can ameliorate TBI by inhibiting ferroptosis and neuroinflammation. Here, our findings suggest that DFO can reduce the accumulation of iron, lipid peroxides, and reactive oxygen species (ROS) and modulate the expression of ferroptosis-related indicators. Moreover, DFO may reduce NLRP3 activation via the ROS/NF-κB pathway, modulate microglial polarization, reduce neutrophil and macrophage infiltration, and inhibit the release of inflammatory factors after TBI. Additionally, DFO may reduce the activation of neurotoxic responsive astrocytes. Finally, we demonstrated that DFO can protect motor memory function, reduce edema and improve peripheral blood perfusion at the site of trauma in mice with TBI, as shown by behavioral experiments such as the Morris water maze test, cortical blood perfusion assessment and animal MRI. In conclusion, DFO ameliorates TBI by reducing iron accumulation to alleviate ferroptosis and neuroinflammation, and these findings provide a new therapeutic perspective for TBI. [ABSTRACT FROM AUTHOR]