CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic target
Circular RNAs (circRNAs) are stable noncoding RNAs that play a crucial role in neurodegenerative diseases, and they have been implicated in the pathogenesis of postoperative cognitive dysfunction (POCD). However, their underlying molecular mechanisms in POCD remain poorly understood. This study iden...
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Elsevier
2025-06-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S216225312500109X |
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| author | Changteng Zhang Xiaoyu Zhu Rui Gao Hai Chen Caiyi Yan Wangyang Liu Lina Yang Xianzheng Zeng Haoran Yang Jin Liu Qi Li Daqing Ma Tao Zhu Chan Chen |
| author_facet | Changteng Zhang Xiaoyu Zhu Rui Gao Hai Chen Caiyi Yan Wangyang Liu Lina Yang Xianzheng Zeng Haoran Yang Jin Liu Qi Li Daqing Ma Tao Zhu Chan Chen |
| author_sort | Changteng Zhang |
| collection | DOAJ |
| description | Circular RNAs (circRNAs) are stable noncoding RNAs that play a crucial role in neurodegenerative diseases, and they have been implicated in the pathogenesis of postoperative cognitive dysfunction (POCD). However, their underlying molecular mechanisms in POCD remain poorly understood. This study identified hsa_circRNA_061570 as significantly upregulated in plasma after anesthesia/surgery using high-throughput circRNA microarray screening, correlating with cognitive decline. Its murine homolog, circITSN1, was further investigated using shRNA-mediated knockdown in the hippocampus. Behavioral tests (open field, Y maze, and fear conditioning) revealed that circITSN1 suppression improved spatial and contextual memory without affecting motor function. Neuronal damage analysis via Golgi staining demonstrated that circITSN1 knockdown alleviated synaptic and dendritic spine impairments. Mechanistically, circITSN1 directly bound to RNA-binding protein EIF4A3, stabilizing Itsn1 mRNA and activating the JNK inflammatory pathway, thereby increasing pro-inflammatory cytokines. Spatial co-localization of circITSN1 with neuronal markers and EIF4A3 underscored its neuron-specific regulatory role. These findings establish circITSN1 as a critical mediator of neuroinflammation through JNK pathway activation, positioning it as both a diagnostic biomarker and a promising therapeutic target for POCD intervention. The study bridges circRNA biology with neurocognitive pathology, offering novel insights into post-surgical cognitive impairment mechanisms. |
| format | Article |
| id | doaj-art-9d2e37c5aad849258ae9d0e9f69837d4 |
| institution | OA Journals |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-9d2e37c5aad849258ae9d0e9f69837d42025-08-20T02:25:13ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-06-0136210255510.1016/j.omtn.2025.102555CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic targetChangteng Zhang0Xiaoyu Zhu1Rui Gao2Hai Chen3Caiyi Yan4Wangyang Liu5Lina Yang6Xianzheng Zeng7Haoran Yang8Jin Liu9Qi Li10Daqing Ma11Tao Zhu12Chan Chen13Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, ChinaDepartment of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, ChinaDepartment of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, ChinaDepartment of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital 610041, Sichuan University, Chengdu, Sichuan, ChinaDepartment of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, ChinaDepartment of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, ChinaDepartment of Anesthesiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, ChinaDepartment of Pain Management, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, ChinaShool of Educational Science, Chongqing Normal University, Chongqing 401331, ChinaDepartment of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, ChinaDepartment of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, ChinaDivision of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London SW72AZ, UKDepartment of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Corresponding author: Tao Zhu, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Centre of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China; Corresponding author: Chan Chen, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.Circular RNAs (circRNAs) are stable noncoding RNAs that play a crucial role in neurodegenerative diseases, and they have been implicated in the pathogenesis of postoperative cognitive dysfunction (POCD). However, their underlying molecular mechanisms in POCD remain poorly understood. This study identified hsa_circRNA_061570 as significantly upregulated in plasma after anesthesia/surgery using high-throughput circRNA microarray screening, correlating with cognitive decline. Its murine homolog, circITSN1, was further investigated using shRNA-mediated knockdown in the hippocampus. Behavioral tests (open field, Y maze, and fear conditioning) revealed that circITSN1 suppression improved spatial and contextual memory without affecting motor function. Neuronal damage analysis via Golgi staining demonstrated that circITSN1 knockdown alleviated synaptic and dendritic spine impairments. Mechanistically, circITSN1 directly bound to RNA-binding protein EIF4A3, stabilizing Itsn1 mRNA and activating the JNK inflammatory pathway, thereby increasing pro-inflammatory cytokines. Spatial co-localization of circITSN1 with neuronal markers and EIF4A3 underscored its neuron-specific regulatory role. These findings establish circITSN1 as a critical mediator of neuroinflammation through JNK pathway activation, positioning it as both a diagnostic biomarker and a promising therapeutic target for POCD intervention. The study bridges circRNA biology with neurocognitive pathology, offering novel insights into post-surgical cognitive impairment mechanisms.http://www.sciencedirect.com/science/article/pii/S216225312500109XMT: Non-coding RNAscircRNApostoperative cognitive dysfunctioncircITSN1intersection 1EIF4A3 |
| spellingShingle | Changteng Zhang Xiaoyu Zhu Rui Gao Hai Chen Caiyi Yan Wangyang Liu Lina Yang Xianzheng Zeng Haoran Yang Jin Liu Qi Li Daqing Ma Tao Zhu Chan Chen CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic target Molecular Therapy: Nucleic Acids MT: Non-coding RNAs circRNA postoperative cognitive dysfunction circITSN1 intersection 1 EIF4A3 |
| title | CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic target |
| title_full | CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic target |
| title_fullStr | CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic target |
| title_full_unstemmed | CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic target |
| title_short | CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic target |
| title_sort | circitsn1 eif4a3 itsn1 axis mediates postoperative cognitive dysfunction in aged mice a novel mechanism and therapeutic target |
| topic | MT: Non-coding RNAs circRNA postoperative cognitive dysfunction circITSN1 intersection 1 EIF4A3 |
| url | http://www.sciencedirect.com/science/article/pii/S216225312500109X |
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