CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic target

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

doi:10.1016/j.omtn.2025.102555

Molecular Therapy: Nucleic Acids (Jun 2025)

CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic target

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

Affiliations

Changteng Zhang: 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
Xiaoyu Zhu: 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
Rui Gao: 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
Hai Chen: Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, West China Hospital 610041, Sichuan University, Chengdu, Sichuan, China
Caiyi Yan: 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
Wangyang Liu: 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
Lina Yang: Department of Anesthesiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu 610072, Sichuan, China
Xianzheng Zeng: Department of Pain Management, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
Haoran Yang: Shool of Educational Science, Chongqing Normal University, Chongqing 401331, China
Jin Liu: 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
Qi Li: 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
Daqing Ma: Division of Anaesthetics, Pain Medicine and Intensive Care, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea and Westminster Hospital, London SW72AZ, UK
Tao Zhu: 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: Tao Zhu, Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
Chan Chen: 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.

DOI: https://doi.org/10.1016/j.omtn.2025.102555
Journal volume & issue: Vol. 36, no. 2
p. 102555

Abstract

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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.

Published in Molecular Therapy: Nucleic Acids

ISSN: 2162-2531 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.cell.com/molecular-therapy-family/nucleic-acids/latest-content

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