USP7 regulates HMOX-1 via deubiquitination to suppress ferroptosis and ameliorate spinal cord injury in rats.

Heme oxygenase 1 (HMOX-1) is overexpressed in spinal cord injury (SCI) and relevant to ferroptosis. Ubiquitin-specific-processing protease 7 (USP7) has unveiled its role in regulating HMOX-1 stabilization while its function in SCI remains unknown. This study is to explore the potential molecular mechanism of the USP7-HMOX-1 axis in ferroptosis in a SCI rat model. SCI was assessed with Basso, Beattie, Bresnahan locomotion evaluation, hematoxylin-eosin histological staining, and immunofluorescence detection of NeuN. Ferroptosis was assessed by detections of the iron content, malondialdehyde and glutathione levels, mitochondrial damage, and glutathione peroxidase 4, 4-hydroxynonenal, USP7, and HMOX-1 expression in spinal cord. Co-immunoprecipitation was used to detect the binding of USP7 to HMOX-1. The ubiquitination level of HMOX-1 was measured after USP7 overexpression. USP7 expression was downregulated and HMOX-1 expression was upregulated in SCI rat models. HMOX-1 or USP7 overexpression promoted motor function recovery, ameliorated spinal cord damage, increased NeuN expression, and blocked the occurrence of ferroptosis in SCI rat models. In SCI rats, USP7 directly bound to HMOX-1 and its overexpression promoted HMOX-1 expression via deubiquitination. To sum up, USP7 overexpression facilitated the expression of HMOX-1 through deubiquitination, thereby reducing ferroptosis and alleviating SCI.