Wang HaoLin, Xia Lei, Huang ZhengNan, Ma YuJie, Yao Ge, Hu ShaoZhen, Dou NingNing, Li ShiTing, Lian Hao, Chen Kui, Zhong Jun
Department of Neurosurgery, XinHua Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, China.
Department of Traditional Chinese Medicine, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Eur J Neurosci. 2025 Aug;62(3):e70209. doi: 10.1111/ejn.70209.
Demyelination is widely acknowledged as the underlying pathological mechanism of trigeminal neuralgia (TN), while ferroptosis has been implicated in neurodegenerative disorders associated with demyelination. However, the precise contribution of ferroptosis to TN-related demyelination has yet to be elucidated. To investigate the putative pathway implicated in neuropathic pain, we conducted RNA-seq analysis in the IoN-CCI rat model that is deemed to simulate the pathology of TN. Subsequently, we explored iron metabolism and the ferroptosis-related pathway in this TN model. Finally, we utilized Ferrostatin-1 and Liproxstatin-1 to suppress ferroptosis and assessed alterations in iron metabolism and myelin sheath integrity through immunohistochemistry and transmission electron microscopy. Our experiments showed that IoN-CCI induced ferroptosis, characterized by increased iron accumulation and decreased expression of GPX4, FPN, and SLC7A11. This resulted in mitochondrial shrinkage in Schwann cells and loosened wrapping of the myelin sheath, as well as activation of neuroinflammation and oxidative stress. Inhibition of ferroptosis reversed these effects and alleviated demyelination and neuropathic pain. In conclusion, our study has clarified the impact of ferroptosis-induced demyelination in TN, providing a potential strategy for treating TN and offering new insights into the study of peripheral nerve demyelination diseases.
脱髓鞘被广泛认为是三叉神经痛（TN）的潜在病理机制，而铁死亡与脱髓鞘相关的神经退行性疾病有关。然而，铁死亡对TN相关脱髓鞘的确切作用尚未阐明。为了研究与神经性疼痛相关的假定途径，我们在被认为模拟TN病理的IoN-CCI大鼠模型中进行了RNA测序分析。随后，我们在这个TN模型中探索了铁代谢和铁死亡相关途径。最后，我们使用铁抑素-1和利普罗他汀-1来抑制铁死亡，并通过免疫组织化学和透射电子显微镜评估铁代谢和髓鞘完整性的变化。我们的实验表明，IoN-CCI诱导了铁死亡，其特征是铁积累增加以及GPX4、FPN和SLC7A11的表达降低。这导致雪旺细胞中线粒体收缩、髓鞘包裹松散，以及神经炎症和氧化应激的激活。抑制铁死亡可逆转这些效应，并减轻脱髓鞘和神经性疼痛。总之，我们的研究阐明了铁死亡诱导的脱髓鞘在TN中的影响，为治疗TN提供了一种潜在策略，并为周围神经脱髓鞘疾病的研究提供了新的见解。
