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journal article·2026-02Open access

TRIM56 Aggravates Cerebral Ischemia‐Reperfusion Injury via Inhibiting KLF4‐Activated Ferroptosis Signaling

Qiangping Wang, Shuang Li, Man Li, Wenke Zhou, Jianqing Zhang, Zhenfu Wu, Zhaoqi Mao, Juan Wan, Xinhao Tang, Baoping Zheng, Qiang Liu, Zhendong Li, Xiaobing Jiang, Qingping Wu, Youfan Ye, Haijun Wang

Advanced Science· Volume 13· Issue 8
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Abstract

Abstract Cerebral ischemia‐reperfusion (I/R) injury often causes significant neuronal damage, neurological deficits, and long‐term disability. This study investigates the role of tripartite motif‐protein 56 (TRIM56) in cerebral I/R injury and elucidates the underlying mechanisms. Here, a significant increase in TRIM56 expression in the human brain, mouse brain, and primary neurons after cerebral I/R injury is first detected. TRIM56 knockout mice exhibit reduced neurological deficits and a diminished inflammatory response, with TRIM56 overexpression intensifying these effects. Mechanistic investigations demonstrate that TRIM56 promotes neuronal ferroptosis by directly interacting with Krüppel‐like factor 4 (KLF4) and triggering its K48‐linked ubiquitination‐dependent degradation. Moreover, compound screening identifies farudodstat as a potential TRIM56 inhibitor to reduce I/R injury in vivo and in vitro. In conclusion, TRIM56 critically regulates neuronal damage during cerebral I/R injury, thereby presenting as a potential therapeutic target for reducing brain I/R injury. Novel therapeutic strategies inhibiting TRIM56 or its downstream signaling pathways may be developed to mitigate the devastating effects of I/R injury on neuronal survival and function.
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Research context

OpenAlex topics: Ferroptosis and cancer prognosis · Neuroinflammation and Neurodegeneration Mechanisms · Inflammasome and immune disorders

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Department of Neurosurgery Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 China

Department of Neurology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 China

Department of Neurosurgery The First Affiliated Hospital of Xinxiang Medical University Weihui Henan 453100 China

Department of Central laboratory Renmin Hospital of Wuhan University Wuhan Hubei 430060 China

State Key Laboratory of North China Crop Improvement and Regulation Hebei Agricultural University Baoding Hebei 071000 China

State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases Gannan Innovation and Translational Medicine Research Institute Gannan Medical University Ganzhou 341000 China

Department of Anesthesiology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan 430022 China

Department of Ophthalmology Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan Hubei 430022 China

Funding

National Natural Science Foundation of China · Natural Science Foundation of Hubei Province

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