Xiong Junjun, Ge Xuhui, Pan Dishui, Zhu Yufeng, Zhou Yitong, Gao Yu, Wang Haofan, Wang Xiaokun, Gu Yao, Ye Wu, Teng Honglin, Zhou Xuhui, Wang Zheng, Liu Wei, Cai Weihua
Department of Orthopedics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Orthopedics, Second Affiliated Hospital of Naval Medical University, Shanghai, China.
Cell Death Differ. 2025 Feb 27. doi: 10.1038/s41418-025-01467-x.
Astrocytic metabolic reprogramming is an adaptation of metabolic patterns to meet increased energy demands, although the role after spinal cord injury (SCI) remains unclear. Analysis of single-cell RNA sequencing (scRNA-seq) data identified an increase in astrocytic glycolysis, while PFKFB3, a key regulator of glycolytic flux, was significantly upregulated following SCI. Loss of PFKFB3 in astrocytes prohibited neuronal energy supply and enhanced neuronal ferroptosis in vitro and expanded infiltration of CD68 macrophages/microglia, exacerbated neuronal loss, and hindered functional recovery in vivo after SCI. Mechanistically, deubiquitinase UCHL1 plays a crucial role in stabilizing and enhancing PFKFB3 expression by cleaving K48-linked ubiquitin chains. Genetic deletion of Uchl1 inhibited locomotor recovery after SCI by suppression of PFKFB3-induced glycolytic reprogramming in astrocytes. Furthermore, the UCHL1/PFKFB3 axis increased lactate production, leading to enhanced histone lactylation and subsequent transcription of Uchl1 and several genes related to glycolysis, suggesting a glycolysis/H4K8la/UCHL1 positive feedback loop. These findings help to clarify the role of the UCHL1/PFKFB3/H4K8la loop in modulation of astrocytic metabolic reprogramming and reveal a potential target for treatment of SCI.
星形胶质细胞代谢重编程是一种代谢模式的适应性变化，以满足增加的能量需求，尽管其在脊髓损伤（SCI）后的作用仍不清楚。单细胞RNA测序（scRNA-seq）数据分析显示星形胶质细胞糖酵解增加，而糖酵解通量的关键调节因子PFKFB3在脊髓损伤后显著上调。星形胶质细胞中PFKFB3的缺失抑制了神经元的能量供应，增强了体外神经元的铁死亡，并扩大了CD68巨噬细胞/小胶质细胞的浸润，加剧了神经元损失，并阻碍了脊髓损伤后体内的功能恢复。机制上，去泛素化酶UCHL1通过切割K48连接的泛素链在稳定和增强PFKFB3表达中起关键作用。Uchl1基因缺失通过抑制星形胶质细胞中PFKFB3诱导的糖酵解重编程来抑制脊髓损伤后的运动恢复。此外，UCHL1/PFKFB3轴增加了乳酸生成，导致组蛋白乳酸化增强以及Uchl1和几个与糖酵解相关基因的转录增加，提示存在糖酵解/H4K8la/UCHL1正反馈环。这些发现有助于阐明UCHL1/PFKFB3/H4K8la环在调节星形胶质细胞代谢重编程中的作用，并揭示脊髓损伤治疗的潜在靶点。
