O-GlcNAcylation Suppressed Apoptosis and Ferroptosis in Traumatic Brain Injury by Enhancing Mitophagy.

O-linked-N-acetylglucosaminylation (O-GlcNAcylation), a distinctive post-translational modification (PTM), is ubiquitously present in numerous nuclear and mitochondrial proteins. The emerging role of O-GlcNAcylation is increasingly recognized for its involvement in various diseases. However, its role in traumatic brain injury (TBI) has not been explored. This study was aimed to explore the neuroprotection of O-GlcNAcylation in both in vivo and in vitro TBI models. Our results revealed that the levels of O-GlcNAcylation were increased after TBI. Up-regulation of O-GlcNAcylation by Thiamet G (TMG) provided neuroprotection after TBI. Moreover, TMG inhibited TBI-triggered blood-brain barrier (BBB) damage. Furthermore, TMG alleviated apoptosis and ferroptosis caused by TBI. Besides, TMG activated mitophagy after TBI, and the neuroprotection of TMG was attenuated when mitophagy was inhibited. Importantly, TMG also attenuated cell death, decreased apoptosis and ferroptosis, and activated mitophagy after TBI in vitro. Taken together, our data provided the first evidence that O-GlcNAcylation played a crucial role in TBI by activation of mitophagy.