Liu Xinjie, Pang Yilin, Fan Baoyou, Zhang Jiawei, Liu Shen, Deng Xiaobing, Li Yun, Liu Ying, Zhang Xu, Zhao Chenxi, Wang Xiaoyu, Wu Xudong, Lai Luhua, Feng Shiqing, Liu Wenpeng, Ning Guangzhi, Yao Xue
Tianjin Key Laboratory of Spine and Spinal Cord, Tianjin Institute of Orthopeadic Innovation and Translation, International Science and Technology Cooperation Base of Spinal Cord Injury, Department of Orthopedics, Tianjin Medical University General Hospital, International Chinese Musculoskeletal Research Society Collaborating Center for Spinal Cord Injury, Tianjin, 300052, China.
College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.
J Orthop Translat. 2025 May 7;52:344-359. doi: 10.1016/j.jot.2025.03.013. eCollection 2025 May.
Spinal cord injury (SCI) exerts severe physical, social, and economic effects on individuals and the healthcare system. While much progress has been made in understanding the pathophysiology of SCI, the regulation of the ferroptosis master regulator, GPX4 (Glutathione Peroxidase 4), remains poorly understood.
In a rat T10 contusion SCI model, GPX4 expression was tracked with western blot and immunofluorescence. Ferroptosis was induced in primary neurons using the GPX4 inhibitor RSL3, and inflammatory cytokine release was measured. Conditioned media from these neurons was applied to microglia to assess activation. The GPX4 activator PKUMDL-LC-102 was administered to SCI rats, with functional recovery evaluated through behavioral tests, MRI, and motor-evoked potentials.
We first reveal a temporal and spatial decrease of GPX4 levels in neurons after SCI. We then demonstrate that GPX4 inhibition leads to primary neuronal ferroptosis, triggering the secretion of pro-inflammatory cytokines that activate microglia. This study represents the initial investigation of GPX4-specific targeted activation, demonstrating its potential to promote functional recovery in contusive SCI by improving neuronal survival and reducing microgliosis.
These findings highlight the significance of GPX4 as a key factor for neuroprotection in the spinal cord. We identified the pivotal role of GPX4 in SCI and realize the neuroprotection via specific GPX4 activation to improve functional recovery .
These findings provide a novel avenue for therapeutic intervention to enhance functional recovery after SCI through GPX4 targeted activation.
脊髓损伤（SCI）对个人及医疗保健系统产生严重的身体、社会和经济影响。虽然在理解SCI的病理生理学方面已取得很大进展，但对铁死亡主调节因子谷胱甘肽过氧化物酶4（GPX4）的调控仍知之甚少。
在大鼠T10挫伤性SCI模型中，采用蛋白质免疫印迹法和免疫荧光法追踪GPX4表达。使用GPX4抑制剂RSL3在原代神经元中诱导铁死亡，并检测炎性细胞因子释放。将这些神经元的条件培养基应用于小胶质细胞以评估其激活情况。对SCI大鼠给予GPX4激活剂PKUMDL-LC-102，通过行为测试、磁共振成像（MRI）和运动诱发电位评估功能恢复情况。
我们首次揭示了SCI后神经元中GPX4水平的时空性降低。然后我们证明，抑制GPX4会导致原代神经元发生铁死亡，触发促炎性细胞因子的分泌，进而激活小胶质细胞。本研究是对GPX4特异性靶向激活的初步研究，证明了其通过改善神经元存活和减少小胶质细胞增生来促进挫伤性SCI功能恢复的潜力。
这些发现突出了GPX4作为脊髓神经保护关键因子的重要性。我们确定了GPX4在SCI中的关键作用，并通过特异性激活GPX4实现神经保护以改善功能恢复。
这些发现为通过靶向激活GPX4来增强SCI后功能恢复的治疗干预提供了一条新途径。
