Ferristatin II, an Iron Uptake Inhibitor, Exerts Neuroprotection against Traumatic Brain Injury via Suppressing Ferroptosis

As a specific ferroptosis marker, transferrin receptor 1 (TfR1) expression is increased following traumatic brain injury (TBI), but the precise role of TfR1 in TBI-induced ferroptosis and neurodegeneration remains to be determined. To further identify more potent ferroptosis inhibitors and effective targets for treating TBI, our study aims at investigating the effects of TfR1 on ferroptosis in a mouse TBI model using ferristatin II (an iron uptake and TfR1 inhibitor). The effect of ferristatin II was first verified in the HT-22 cell line in vitro and showed antiferroptotic action when exposed to ferric citrate (FAC), which is in parallel with the results obtained from the positive controls, including deferoxamine (DFO) and liproxstatin-1 (Lip-1). In vivo, ferristatin II administration reduced the expression of TfR1 at 12 h after TBI, and immunofluorescence experiments further confirmed that this decreased TfR1-positive cells were neurons. Importantly, ferristatin II suppressed TBI-induced iron homeostatic imbalance by decreasing the content of Fe (III) and iron-positive deposits and reversed the expression of iron homeostasis-related proteins. Moreover, ferristatin II attenuated TBI-induced lipid peroxidation by reversing the expression of lipid peroxidative genes and proteins, as well as the increase in malondialdehyde (MDA) level following TBI. Finally, ferristatin II alleviated TBI-induced neuronal injury and neurodegeneration, as detected by staining with Nissl and Fluoro-Jade B, thereby exerting a neuroprotective effect. In summary, these data indicated that ferristatin II might be a potential strategy to restrain ferroptosis and develop novel therapeutic agents against TBI.