Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.
National Center for Neurological Disorders, Beijing, China.
J Cell Mol Med. 2024 May;28(10):e18396. doi: 10.1111/jcmm.18396.
Previous studies have found that ferroptosis plays an important role in a variety of neurological diseases. However, the precise role of ferroptosis in the multiple sclerosis patients remains uncertain. We defined and validated a computational metric of ferroptosis levels. The ferroptosis scores were computed using the AUCell method, which reflects the enrichment scores of ferroptosis-related genes through gene ranking. The reliability of the ferroptosis score was assessed using various methods, involving cells induced to undergo ferroptosis by six different ferroptosis inducers. Through a comprehensive approach integrating snRNA-seq, spatial transcriptomics, and spatial proteomics data, we explored the role of ferroptosis in multiple sclerosis. Our findings revealed that among seven sampling regions of different white matter lesions, the edges of active lesions exhibited the highest ferroptosis score, which was associated with activation of the phagocyte system. Remyelination lesions exhibit the lowest ferroptosis score. In the cortex, ferroptosis score were elevated in neurons, relevant to a variety of neurodegenerative disease-related pathways. Spatial transcriptomics demonstrated a significant co-localization among ferroptosis score, neurodegeneration and microglia, which was verified by spatial proteomics. Furthermore, we established a diagnostic model of multiple sclerosis based on 24 ferroptosis-related genes in the peripheral blood. Ferroptosis might exhibits a dual role in the context of multiple sclerosis, relevant to both neuroimmunity and neurodegeneration, thereby presenting a promising and novel therapeutic target. Ferroptosis-related genes in the blood that could potentially serve as diagnostic and prognostic markers for multiple sclerosis.
先前的研究发现铁死亡在多种神经退行性疾病中发挥着重要作用。然而，铁死亡在多发性硬化症患者中的确切作用尚不清楚。我们定义并验证了一种铁死亡水平的计算指标。铁死亡评分是通过 AUCell 方法计算的，该方法通过基因排序反映铁死亡相关基因的富集评分。通过使用涉及六种不同铁死亡诱导剂诱导细胞发生铁死亡的各种方法来评估铁死亡评分的可靠性。通过整合 snRNA-seq、空间转录组学和空间蛋白质组学数据的综合方法，我们探索了铁死亡在多发性硬化症中的作用。我们的研究结果表明，在七个不同的白质病变采样区域中，活性病变的边缘表现出最高的铁死亡评分，这与吞噬细胞系统的激活有关。髓鞘再生病变的铁死亡评分最低。在大脑皮层中，神经元中铁死亡评分升高，与多种神经退行性疾病相关途径有关。空间转录组学显示铁死亡评分、神经退行性变和小胶质细胞之间存在显著的共定位，这通过空间蛋白质组学得到了验证。此外，我们基于外周血中的 24 个铁死亡相关基因建立了多发性硬化症的诊断模型。铁死亡在多发性硬化症的背景下可能发挥双重作用，与神经免疫和神经退行性变都有关，从而为治疗提供了一个有前景的新靶点。血液中的铁死亡相关基因可能成为多发性硬化症的诊断和预后标志物。
