Objective Ferroptosis plays an important role in traumatic brain injury (TBI). The p53 protein is a major mediator of ferroptosis. However, the role of p53mediated ferroptosis in TBI has not been studied. Sirtuin 2 (SIRT2) exerts a protective effects role in TBI, although the underlying mechanism of this protection remains unclear. In the present study, we tested the hypothesis that that SIRT2 mitigates TBI by regulating p53-mediated ferroptosis. Methods and resultsTo model TBI in mice, we used the controlled cortical impact (CCI) injury method. We found that ferroptosis was significantly activated by CCI, and peaked 3 days following CCI, as evidenced by upregulation of GPX4 and SLC7A11, increased content of decreases glutathione, lipid peroxidation, malondialdehyde and ferrous ion. Inhibition of ferroptosis significantly alleviated neurological indications and brain edema. In addition, knockout of p53 significantly blocked ferroptosis following CCI. Furthermore, we found that inhibition of SIRT2 upregulated the acetylation of p53, as well as p53 expression, and exacerbated ferroptosis following CCI. Interestingly, knockout of p53 rescued the SIRT2 inhibition-induced exacerbation of ferroptosis. ConclusionsThese findings indicate that p53mediated ferroptosis contributes to the pathogenesis of TBI. Furthermore, we demonstrate that SIRT2 exerts a neuroprotective effect against TBI by suppressing p53-mediated ferroptosis.

Recently, several studies have reported that the pharmacological effects exerted by cannabidiol (CBD) are partially related to the regulation of autophagy. Increasing evidence indicates that autophagy provides protection against ischemia‐induced brain injury. However, the protective effect of CBD against mitochondrial‐dependent apoptosis in hemorrhagic shock (HS)‐induced brain injury has not been studied. In the present study, we observed the protective effects of CBD against neural mitochondrial‐dependent apoptosis in a rat model of HS. In addition, CBD increased Beclin‐1 and LC3II expression and reduced P62 expression, which were indicative of autophagy. CBD treatment attenuated the neural apoptosis induced by HS, as reflected by restoring mitochondrial dysfunction, downregulation of BAX, neuro‐apoptosis ratio and NF‐κB signaling activation, and upregulation of BCL2 in the cerebral cortex. Such protective effects were reversed by 3‐Methyladenine, a specific autophagy inhibitor, indicating that the protective effects of CBD treatment involved autophagy. LY294002, a PI3K inhibitor, significantly inhibited CBD‐induced autophagy, demonstrating that PI3K/AKT signaling is involved in the CBD’s regulation of autophagy. Furthermore, we found that CBD treatment upregulated PI3K/AKT signaling via cannabinoid receptor 1. Therefore, these findings suggested that CBD treatment protects against cerebral injury induced by HS‐mediated mitochondrial‐dependent apoptosis by activating the PI3K/AKT signaling pathway to reinforce autophagy.