TP53 drives neuronal ferroptosis by promoting KLHL4-mediated SLC7A11 ubiquitination after spinal cord injury

Ferroptosis constitutes a pivotal pathological event following spinal cord injury and presents substantial challenges to the restoration of neurological function. Cystine-glutamate transporter SLC7A11 is essential for maintaining cellular redox homeostasis and resisting Ferroptosis. However, the mechanisms underlying neuronal Ferroptosis caused by SLC7A11 downregulation following spinal cord injury remain unclear. Herein, we provide evidence that tumor protein 53, a negative regulator of SLC7A11, was significantly upregulated post-spinal cord injury. Transcriptomic analysis indicated that tumor protein 53 was associated with injury severity. We subsequently confirmed that tumor protein 53 inhibition restored the expressions of SLC7A11 and Glutathione Peroxidase 4, alleviated neuronal Ferroptosis, and improved neurological function in a contusion spinal cord injury rat model. The regulatory effects of tumor protein 53 on the transcription and ubiquitination of SLC7A11 were further elucidated using chromatin immunoprecipitation polymerase chain reaction and cleavage under targets and tagmentation techniques. Additionally, Kelch-like protein 4, an E3 ubiquitin Ligase adaptor, was demonstrated to play an important role in the tumor protein 53-mediated ubiquitination of SLC7A11. In summary, the present study elucidated the possible mechanisms of tumor protein 53-mediated neuronal Ferroptosis in spinal cord injury, thereby providing potential targets and insights for clinical translation.

Kelch-like protein 4; SLC7A11; bioinformatics; ferroptosis; glutathione peroxidase 4; nerve regeneration; neuronal survival; spinal cord injury; tumor protein 53; ubiquitination.