Zhao Yao, Chen Feixiang, Chen Chen, Yang Yuling, Wang Luo, Zhu Jiaqi, Wang Xin, Liu Yanyan, Ding Jing
Department of Neurology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
Department of Materials Science and State Key Laboratory of Molecular Engineering of Polymers, Academy for Engineering and Technology, Fudan University, Shanghai, 200433, China.
J Nanobiotechnology. 2025 Jun 11;23(1):436. doi: 10.1186/s12951-025-03408-9.
Seizures induce significant immune and metabolic stress in microglia, but the interaction between these processes remains unclear. This study, utilizing single-nucleus RNA sequencing data from temporal lobe epilepsy (TLE) patients, reveals that reactive oxygen species (ROS) stabilize hypoxia-inducible factor 1-alpha (HIF-1α), thereby inducing glycometabolic reprogramming in microglia and driving the development of a pro-inflammatory phenotype. To address this, a coordination acid-engineered Prussian Blue (PB@ZIF) nanosystem is developed, where Zn²⁺ sites in the zeolitic imidazolate framework (ZIF) lower the local pKa, thereby enhancing the reaction efficiency of PB with free radicals. In vivo experiments using a TLE model demonstrate that PB@ZIF is effectively internalized by microglia and significantly alleviates spontaneous recurrent seizures and seizure-related behaviors. PB@ZIF mitigates microglial inflammatory activation and reduces neuronal injury. Notably, PB@ZIF-induced ROS reduction enhances the enzymatic activity of prolyl hydroxylase domain enzymes, effectively inhibiting HIF-1α-driven glycometabolic reprogramming in microglia. This study identifies a molecular mechanism underlying the immune-metabolic interactions in epilepsy and proposes a promising therapeutic strategy regulating microglial metabolism to improve epilepsy management.
癫痫发作会在小胶质细胞中引发显著的免疫和代谢应激，但这些过程之间的相互作用仍不清楚。本研究利用颞叶癫痫（TLE）患者的单核RNA测序数据，揭示活性氧（ROS）可稳定缺氧诱导因子1α（HIF-1α），从而诱导小胶质细胞中的糖代谢重编程并驱动促炎表型的发展。为了解决这个问题，开发了一种配位酸工程化普鲁士蓝（PB@ZIF）纳米系统，其中沸石咪唑酯骨架（ZIF）中的Zn²⁺位点降低了局部pKa，从而提高了PB与自由基的反应效率。使用TLE模型进行的体内实验表明，PB@ZIF能被小胶质细胞有效内化，并显著减轻自发性反复癫痫发作和与癫痫相关的行为。PB@ZIF减轻了小胶质细胞的炎症激活并减少了神经元损伤。值得注意的是，PB@ZIF诱导的ROS减少增强了脯氨酰羟化酶结构域酶的酶活性，有效抑制了HIF-1α驱动的小胶质细胞糖代谢重编程。本研究确定了癫痫中免疫-代谢相互作用的分子机制，并提出了一种有前景的治疗策略，即调节小胶质细胞代谢以改善癫痫治疗。
