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Objective <p>Ischemic stroke is a leading cause of neurological disability and death worldwide, posing a substantial threat to human health. Tripartite motif-containing protein 7 (Trim7), an E3 ubiquitin ligase, is involved in the progression of various diseases, but its role in ischemic stroke remains unknown. This study aims to investigate the functional significance and molecular mechanism of Trim7 in ischemia-induced neuronal injury.</p> Methods <p>Trim7 knockout mice underwent transient middle cerebral artery occlusion-reperfusion, and adenovirus-mediated Trim7 knockdown or overexpression was performed in rat primary cortical neurons subjected to oxygen–glucose deprivation/reoxygenation. Ferroptosis markers, redox status, and neuronal injury were systematically evaluated. The interaction between Trim7 and heat shock protein family member A5 (HSPA5) was examined using co-immunoprecipitation, GST pull-down, and ubiquitination assays.</p> Results <p>Trim7 protein was significantly upregulated in cerebral ischemia–reperfusion models. Trim7 deletion or knockdown alleviated neuronal injury, reduced lipid peroxidation and inflammation, and restored glutathione peroxidase 4 (GPX4) protein expression and activity, thereby suppressing ferroptosis. In contrast, Trim7 overexpression exacerbated ferroptotic and inflammatory responses. Mechanistically, Trim7 directly interacted with HSPA5 via its PRY/SPRY domain and the substrate-binding domain of HSPA5, and promoted K48-linked polyubiquitination of HSPA5, leading to its proteasome-dependent degradation.</p> Conclusion <p>This study is the first to identify the Trim7–HSPA5–GPX4 axis as a previously unrecognized regulatory pathway that promotes ischemic-reperfusion nuernoal injury through ferroptosis. These findings provide novel mechanistic insights into the pathogenesis and potential therapeutic strategies of ischemic stroke.</p>

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Trim7 aggravates ischemic stroke–associated ferroptosis by promoting ubiquitin-mediated degradation of HSPA5

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月22日

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  • Wenxuan Lu,
  • Sha Hu,
  • Wenhui Zhang,
  • Ruiqiang Wang,
  • Dongxu Zhao,
  • Peng Ji,
  • Peng Zhang,
  • Yilin Zhang,
  • Huili Gao,
  • Ziliang Wang,
  • Tianxiao Li,
  • Zhigang Lu,
  • Zhaoshuo Li

摘要

Objective

Ischemic stroke is a leading cause of neurological disability and death worldwide, posing a substantial threat to human health. Tripartite motif-containing protein 7 (Trim7), an E3 ubiquitin ligase, is involved in the progression of various diseases, but its role in ischemic stroke remains unknown. This study aims to investigate the functional significance and molecular mechanism of Trim7 in ischemia-induced neuronal injury.

Methods

Trim7 knockout mice underwent transient middle cerebral artery occlusion-reperfusion, and adenovirus-mediated Trim7 knockdown or overexpression was performed in rat primary cortical neurons subjected to oxygen–glucose deprivation/reoxygenation. Ferroptosis markers, redox status, and neuronal injury were systematically evaluated. The interaction between Trim7 and heat shock protein family member A5 (HSPA5) was examined using co-immunoprecipitation, GST pull-down, and ubiquitination assays.

Results

Trim7 protein was significantly upregulated in cerebral ischemia–reperfusion models. Trim7 deletion or knockdown alleviated neuronal injury, reduced lipid peroxidation and inflammation, and restored glutathione peroxidase 4 (GPX4) protein expression and activity, thereby suppressing ferroptosis. In contrast, Trim7 overexpression exacerbated ferroptotic and inflammatory responses. Mechanistically, Trim7 directly interacted with HSPA5 via its PRY/SPRY domain and the substrate-binding domain of HSPA5, and promoted K48-linked polyubiquitination of HSPA5, leading to its proteasome-dependent degradation.

Conclusion

This study is the first to identify the Trim7–HSPA5–GPX4 axis as a previously unrecognized regulatory pathway that promotes ischemic-reperfusion nuernoal injury through ferroptosis. These findings provide novel mechanistic insights into the pathogenesis and potential therapeutic strategies of ischemic stroke.