Department of Spinal Surgery, First Affiliated Hospital of Fujian Medical University, Fujian, Fuzhou, 350005, PR China.
Department of Spinal Surgery, Affiliated Sanming First Hospital of Fujian Medical University, Sanming, Fujian, 365000, PR China.
Neurochem Int. 2023 Sep;168:105554. doi: 10.1016/j.neuint.2023.105554. Epub 2023 May 29.
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.
血红素加氧酶 1（HMOX-1）在脊髓损伤（SCI）中过度表达，与铁死亡有关。泛素特异性加工蛋白酶 7（USP7）已揭示其在调节 HMOX-1 稳定中的作用，但其在 SCI 中的作用尚不清楚。本研究旨在探索 USP7-HMOX-1 轴在 SCI 大鼠模型中铁死亡中的潜在分子机制。通过 Basso、Beattie、Bresnahan 运动评估、苏木精-伊红组织染色和 NeuN 免疫荧光检测评估 SCI。通过铁含量、丙二醛和谷胱甘肽水平、线粒体损伤以及谷胱甘肽过氧化物酶 4、4-羟基壬烯醛、USP7 和 HMOX-1 在脊髓中的表达检测铁死亡。用免疫共沉淀检测 USP7 与 HMOX-1 的结合。测量 USP7 过表达后 HMOX-1 的泛素化水平。在 SCI 大鼠模型中，下调 USP7 表达和上调 HMOX-1 表达。HMOX-1 或 USP7 过表达促进运动功能恢复，改善脊髓损伤，增加 NeuN 表达，并阻断 SCI 大鼠铁死亡的发生。在 SCI 大鼠中，USP7 直接与 HMOX-1 结合，其过表达通过去泛素化促进 HMOX-1 表达。总之，USP7 过表达通过去泛素化促进 HMOX-1 的表达，从而减少铁死亡并缓解 SCI。
