TRIM56 Aggravates Cerebral Ischemia‐Reperfusion Injury via Inhibiting KLF4‐Activated Ferroptosis Signaling
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.
Authors
- Juan Wan (ORCID: https://orcid.org/0000-0002-6187-5113)
- Xiaolong Tang (ORCID: https://orcid.org/0000-0002-4744-5846)
- Zhenxing Mao (ORCID: https://orcid.org/0000-0001-5171-1169)
- Youfan Ye (ORCID: https://orcid.org/0000-0003-3136-8353)
- Qiangping Wang (ORCID: https://orcid.org/0000-0002-9728-4075)
- Qingping Wu (ORCID: https://orcid.org/0000-0002-9164-1051)
- Baoping Zheng (ORCID: https://orcid.org/0000-0003-4294-1442)
- Z D Li
- Zhongxue Wu (ORCID: https://orcid.org/0009-0006-4463-6395)
- Man Li (ORCID: https://orcid.org/0000-0003-4041-0437)
- Qiang Liu (ORCID: https://orcid.org/0000-0002-1625-6436)
- Shuang Li (ORCID: https://orcid.org/0000-0001-5164-7216)
- Haijun Wang (ORCID: https://orcid.org/0000-0001-7137-4032)
- Xiaobing Jiang (ORCID: https://orcid.org/0000-0001-9844-2189)
- Jianqing Zhang (ORCID: https://orcid.org/0000-0002-5822-2218)
- Wenke Zhou (ORCID: https://orcid.org/0000-0003-0455-2809)
Institutions
- Hebei Agricultural University (CN)
- Union Hospital (HK)
- Wuhan University (CN)
- Gannan Medical University (CN)
- First Affiliated Hospital of Xinxiang Medical University (CN)
- Wuhan Union Hospital (CN)
- Renmin Hospital of Wuhan University (CN)
- Union Hospital (CN)
- Huazhong University of Science and Technology (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-11-10
- DOI
- https://doi.org/10.1002/advs.202509906
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Hubei Province