Li Shengyou, Gao Xue, Zheng Yi, Yang Yujie, Gao Jianbo, Geng Dan, Guo Lingli, Ma Teng, Hao Yiming, Wei Bin, Huang Liangliang, Wei Yitao, Xia Bing, Luo Zhuojing, Huang Jinghui
Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
J Pharm Anal. 2024 Jan;14(1):86-99. doi: 10.1016/j.jpha.2023.08.006. Epub 2023 Aug 11.
A major impedance to neuronal regeneration after peripheral nerve injury (PNI) is the activation of various programmed cell death mechanisms in the dorsal root ganglion. Ferroptosis is a form of programmed cell death distinguished by imbalance in iron and thiol metabolism, leading to lethal lipid peroxidation. However, the molecular mechanisms of ferroptosis in the context of PNI and nerve regeneration remain unclear. Ferroportin (Fpn), the only known mammalian nonheme iron export protein, plays a pivotal part in inhibiting ferroptosis by maintaining intracellular iron homeostasis. Here, we explored and the involvement of Fpn in neuronal ferroptosis. We first delineated that reactive oxygen species at the injury site induces neuronal ferroptosis by increasing intracellular iron via accelerated UBA52-driven ubiquitination and degradation of Fpn, and stimulation of lipid peroxidation. Early administration of the potent arterial vasodilator, hydralazine (HYD), decreases the ubiquitination of Fpn after PNI by binding to UBA52, leading to suppression of neuronal cell death and significant acceleration of axon regeneration and motor function recovery. HYD targeting of ferroptosis is a promising strategy for clinical management of PNI.
外周神经损伤（PNI）后神经元再生的一个主要障碍是背根神经节中各种程序性细胞死亡机制的激活。铁死亡是一种程序性细胞死亡形式，其特征是铁和硫醇代谢失衡，导致致命的脂质过氧化。然而，在PNI和神经再生背景下铁死亡的分子机制仍不清楚。铁转运蛋白（Fpn）是唯一已知的哺乳动物非血红素铁输出蛋白，通过维持细胞内铁稳态在抑制铁死亡中起关键作用。在此，我们探讨了Fpn在神经元铁死亡中的作用及参与机制。我们首先阐明，损伤部位的活性氧通过加速UBA52驱动的Fpn泛素化和降解增加细胞内铁，并刺激脂质过氧化，从而诱导神经元铁死亡。早期给予强效动脉血管扩张剂肼屈嗪（HYD），通过与UBA52结合减少PNI后Fpn的泛素化，导致神经元细胞死亡受到抑制，轴突再生和运动功能恢复显著加速。靶向铁死亡的HYD是PNI临床治疗的一种有前景的策略。
