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

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

  • Prog Neurobiol. 2025 Dec 11:257:102869. doi: 10.1016/j.pneurobio.2025.102869.
Jiaojiao Wang 1,  Chunfang Dai 2,  Hao Yuan 3,  Qiuyun Tian 3,  Qian Xiao 3,  Xiaohuan Li 3,  Xiuyu Shi 4,  Zhifang Dong 5
Affiliations

Affiliations

  • 1 Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Municipal Health Commission Key Laboratory of Perinatal Medicine, Chongqing 401147, China; Nantong First People's Hospital, Nantong 226001, China.
  • 2 Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Department of Children Health Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong, Guangzhou 510623, China.
  • 3 Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China.
  • 4 Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China. Electronic address: [email protected].
  • 5 Growth, Development, and Mental Health of Children and Adolescence Center, Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing Key Laboratory of Child Neurodevelopment and Cognitive Disorders, Children's Hospital of Chongqing Medical University, Chongqing 400014, China; Chongqing Municipal Health Commission Key Laboratory of Perinatal Medicine, Chongqing 401147, China. Electronic address: [email protected].
PMID: 41390137 DOI: 10.1016/j.pneurobio.2025.102869
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.

Keywords

Hypoxic-ischemic; SCAP/SREBP1; YAP.

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