ArticleCell & bioscience2025
Trim7 aggravates ischemic stroke-associated ferroptosis by promoting ubiquitin-mediated degradation of HSPA5.
Article in Cell & bioscience, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
What it found
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Who cites it
3 citing papers in PubMed.
- Ubiquitination-dependent regulation of ferroptosis in ischemic heart and brain.Redox biology · 2026Review
- Death-associated protein kinase 2 (DAPK2) propagates endoplasmic reticulum stress in macrophages to worsen sepsis through HSPA5-IRE1α axis.Molecular biomedicine · 2026Article
- Glutathione peroxidase 4 as an emerging therapeutic target in osteoarthritis: focus on ferroptosis.Frontiers in cell and developmental biology · 2025Review
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Authors and funding
13 authors.
Funding
Abstract
objectiveIschemic 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.
methodsTrim7 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.
resultsTrim7 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.
conclusionThis 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.
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