Zhang Na, Zhang Saishou, Liu Xiaotong, Zuo Yuan-Yuan, Cui Yan-Ge, Wang Fudi, Zhang Jian-Hua, Chang Yan-Zhong, Yu Peng
Ministry of Education Key Laboratory of Molecular and Cellular Biology, The Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, Hebei Research Center of the Basic Discipline of Cell Biology, College of Life Sciences, Hebei Normal University, No. 20 Nan'erhuan Eastern Road, Shijiazhuang, 050024, Hebei Province, China.
The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, 10058, China.
Free Radic Biol Med. 2025 Oct;238:370-386. doi: 10.1016/j.freeradbiomed.2025.06.055. Epub 2025 Jul 1.
Trace element iron is essential for the proper functioning of oligodendrocytes. Ferroportin1 (FPN1), the only known iron-exporting protein, plays a critical role in maintaining iron homeostasis within these cells. Conditional knockout of the Ferroportin1 gene in oligodendrocytes (Fpn1-cKO) induced significant depression-like behavior in mice. Moreover, a marked decrease in myelin basic protein (MBP) expression was observed in the corpus callosum, a region enriched with oligodendrocytes. This reduction was accompanied by disrupted myelin structure and cellular hyperpolarization, potentially linked to the activation of the MAPK/ERK, AKT/JNK, and NF-κB signaling pathways triggered by elevated intracellular iron levels and oxidative stress. In vitro studies using the human oligodendrocyte cell line MO3.13 demonstrated that FPN1 silencing increased intracellular iron accumulation, leading to elevated reactive oxygen species (ROS) and activation of both MAPK/ERK and pro-inflammatory signaling pathways. Pharmacological suppression of the β-Catenin pathway using ICG-001 established NF-κB as its downstream signaling mediator. The inflammatory response in oligodendrocytes may further activate microglia and the intracellular IL-6/STAT3 pathway, resulting in upregulated hepcidin mRNA levels in the prefrontal cortex (PFC) and hippocampus. Consequently, iron deficiency in these brain regions impaired electrical conduction in mice. Additionally, impaired synaptic formation in the PFC and hippocampus contributed to the observed depression-like phenotypes in mice. This study highlights the pivotal role of FPN1 in iron efflux from oligodendrocytes. FPN1 deficiency-induced iron overload exacerbates ROS production, triggering neuroinflammation, which may potentiate microglial activation and the IL-6/STAT3 pathway. The subsequent hepcidin-mediated iron sequestration reduces iron availability in the PFC and hippocampus, ultimately disrupting synaptogenesis and neuronal excitability, and culminating in depression-like behaviors.
微量元素铁对少突胶质细胞的正常功能至关重要。铁转运蛋白1（FPN1）是唯一已知的铁输出蛋白，在维持这些细胞内的铁稳态中起关键作用。少突胶质细胞中铁转运蛋白1基因的条件性敲除（Fpn1-cKO）在小鼠中诱导出显著的抑郁样行为。此外，在富含少突胶质细胞的胼胝体中观察到髓鞘碱性蛋白（MBP）表达明显降低。这种减少伴随着髓鞘结构破坏和细胞超极化，这可能与细胞内铁水平升高和氧化应激触发的MAPK/ERK、AKT/JNK和NF-κB信号通路激活有关。使用人少突胶质细胞系MO3.13进行的体外研究表明，FPN1沉默会增加细胞内铁积累，导致活性氧（ROS）升高以及MAPK/ERK和促炎信号通路激活。使用ICG-001对β-连环蛋白途径进行药理学抑制确定NF-κB为其下游信号介质。少突胶质细胞中的炎症反应可能进一步激活小胶质细胞和细胞内IL-6/STAT3途径，导致前额叶皮质（PFC）和海马体中hepcidin mRNA水平上调。因此，这些脑区的铁缺乏会损害小鼠的电传导。此外，PFC和海马体中突触形成受损导致了小鼠中观察到的抑郁样表型。这项研究强调了FPN1在少突胶质细胞铁外流中的关键作用。FPN1缺乏诱导的铁过载会加剧ROS产生，引发神经炎症，这可能增强小胶质细胞激活和IL-6/STAT3途径。随后hepcidin介导的铁螯合降低了PFC和海马体中的铁可用性，最终破坏突触发生和神经元兴奋性，并导致抑郁样行为。
