The YAP/SCAP/SREBP1 pathway in astrocytes: A novel target for treating neonatal hypoxic-ischemic encephalopathy

IF 4.6 2区医学 Q1 NEUROSCIENCES

Progress in Neurobiology Pub Date : 2026-02-01 Epub Date: 2025-12-11 DOI:10.1016/j.pneurobio.2025.102869

Jiaojiao Wang , Chunfang Dai , Hao Yuan , Qiuyun Tian , Qian Xiao , Xiaohuan Li , Xiuyu Shi , Zhifang Dong

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Abstract

Astrocytes play a significant role in the pathogenesis of hypoxic-ischemic encephalopathy (HIE), contributing to neuroexcitotoxicity and inflammatory responses. However, the specific pathways through which astrocytes influence neurons remain incompletely understood. In this study, we found that Yes-associated protein (YAP) was down-regulated and inactivated in hippocampal astrocytes in a hypoxic-ischemic brain damage (HIBD) rat model, as well as in astrocytes subjected to oxygen-glucose deprivation (OGD). Overexpression of YAP in astrocytes reduced neuronal death and improved motor, learning and memory dysfunction deficits associated with HIE. Further investigation demonstrated that YAP exerts neuroprotective effects by modulating lipid metabolism through the SCAP/SREBP1 pathway. Ultimately, activating YAP signaling by XMU-MP-1, a Hippo kinase MST1/2 inhibitor, partially restored brain tissue integrity and function, as well as improved motor, learning and memory functions in HIBD rats. In conclusion, our study has identified a novel YAP/SCAP/SREBP1 pathway that plays neuroprotective roles in HIE.

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星形胶质细胞中的YAP/SCAP/SREBP1通路：治疗新生儿缺氧缺血性脑病的新靶点

星形胶质细胞在缺氧缺血性脑病（HIE）的发病机制中发挥重要作用，参与神经兴奋毒性和炎症反应。然而，星形胶质细胞影响神经元的具体途径仍不完全清楚。在本研究中，我们发现缺氧缺血性脑损伤（HIBD）大鼠模型海马星形胶质细胞中yess相关蛋白（YAP）下调和失活，以及在氧-葡萄糖剥夺（OGD）的星形胶质细胞中。YAP在星形胶质细胞中的过度表达可减少神经元死亡，改善HIE相关的运动、学习和记忆功能障碍缺陷。进一步研究表明，YAP通过SCAP/SREBP1通路调节脂质代谢发挥神经保护作用。最终，通过XMU-MP-1（一种Hippo激酶MST1/2抑制剂）激活YAP信号，部分恢复了HIBD大鼠的脑组织完整性和功能，并改善了运动、学习和记忆功能。总之，我们的研究已经确定了一个新的YAP/SCAP/SREBP1通路，在HIE中起神经保护作用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Progress in Neurobiology 医学-神经科学

CiteScore

12.80

自引率

1.50%

发文量

107

审稿时长

33 days

期刊介绍： Progress in Neurobiology is an international journal that publishes groundbreaking original research, comprehensive review articles and opinion pieces written by leading researchers. The journal welcomes contributions from the broad field of neuroscience that apply neurophysiological, biochemical, pharmacological, molecular biological, anatomical, computational and behavioral analyses to problems of molecular, cellular, developmental, systems, and clinical neuroscience.