Xia Qian, Que Mengxin, Zhan Gaofeng, Zhang Longqing, Zhang Xue, Zhao Yilin, Zhou Huijuan, Zheng Lu, Mao Meng, Li Xing
Department of Anesthesiology and Pain Medicine, Hubei Key Laboratory of Geriatric Anesthesia and Perioperative Brain Health, and Wuhan Clinical Research Center for Geriatric Anesthesia, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Department of Neurobiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
Adv Sci (Weinh). 2025 Feb;12(7):e2410410. doi: 10.1002/advs.202410410. Epub 2024 Dec 24.
Oxidative stress is believed to play critical pathophysiological roles in ischemic brain injury, and the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway is recognized as the most crucial endogenous antioxidant stress damage route. Some research have demonstrated that Nrf2 play critical roles in oxidative stress after ischemic stroke, but the underlying mechanism are not fully elucidated. This study reveals that Nrf2 is modified by SUMOylation and identifies Sentrin/SUMO-specific protease 6 (SENP6) as a negative regulator of Nrf2 SUMOylation. Notably, SENP6 binds to and mediates the deSUMOylation of Nrf2, which in turn inhibits antioxidant response by enhancing ubiquitination-dependent degradation of Nrf2, thereby reducing its transcriptional activity, inducing oxidative stress and aggravating neuronal apoptosis after ischemic stroke. Additionally, blocking the interaction between SENP6 and Nrf2 with a cell membrane-permeable peptide (Tat-Nrf2) preserves the SUMOylation of Nrf2, effectively attenuates oxidative stress, and rescues neurological functions in mice subjected to ischemic stroke. Furthermore, no toxicity is observed when high doses Tat-Nrf2 are injected into nonischemic mice. Collectively, this study uncovers a previously unidentified mechanism whereby SUMOylation of Nrf2 regulates oxidative stress and strongly indicates that interventions targeting SENP6 or its interaction with Nrf2 may provide therapeutic benefits for ischemic stroke.
氧化应激被认为在缺血性脑损伤中起关键的病理生理作用，核因子红细胞2相关因子2（Nrf2）信号通路被认为是最重要的内源性抗氧化应激损伤途径。一些研究表明，Nrf2在缺血性中风后的氧化应激中起关键作用，但其潜在机制尚未完全阐明。本研究揭示Nrf2被小泛素样修饰物（SUMO）化修饰，并确定Sentrin/SUMO特异性蛋白酶6（SENP6）是Nrf2 SUMO化修饰的负调控因子。值得注意的是，SENP6与Nrf2结合并介导其去SUMO化修饰，进而通过增强Nrf2的泛素化依赖性降解来抑制抗氧化反应，从而降低其转录活性，诱导氧化应激并加重缺血性中风后的神经元凋亡。此外，用细胞膜穿透肽（Tat-Nrf2）阻断SENP6与Nrf2之间的相互作用可保留Nrf2的SUMO化修饰，有效减轻氧化应激，并挽救缺血性中风小鼠的神经功能。此外，将高剂量的Tat-Nrf2注射到非缺血小鼠中未观察到毒性。总之，本研究揭示了一种以前未被发现的机制，即Nrf2的SUMO化修饰调节氧化应激，并强烈表明针对SENP6或其与Nrf2相互作用的干预措施可能为缺血性中风提供治疗益处。
