ArticleJournal of inflammation research2025
Cuproptosis and Immune Microenvironment Interplay in Temporal Lobe Epilepsy: Identification of Key Molecular Signatures and Therapeutic Targets.
Article in Journal of inflammation research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.
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Who cites it
1 citing paper in PubMed.
- Nuclear accumulation of PANK4 in hippocampal astrocytes aggravates cuproptosis in association with mild cognitive impairment in aged mice.Frontiers in aging neuroscience · 2026Article
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6 authors.
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Abstract
Background: Temporal lobe epilepsy (TLE), the predominant drug-resistant focal epilepsy, involves neuroinflammation and neuronal hyperexcitability. Cuproptosis-a copper-dependent cell death pathway triggered by mitochondrial copper overload and lipoylated protein aggregation-remains unexplored in epilepsy. This study investigates its molecular basis, neuroinflammatory crosstalk, and therapeutic implications in TLE. Methods: Bulk RNA-seq and single-cell RNA-seq datasets from GEO were analyzed using weighted gene co-expression network analysis (WGCNA) and consensus clustering to stratify cuproptosis-associated TLE subtypes. Ten machine learning algorithms identified hub genes linked to cuproptosis-immune crosstalk. Experimental validation in a pilocarpine-induced TLE mouse model confirmed gene expression changes via Western blot and immunohistochemistry. Results: Two TLE subtypes were stratified: cuproptosis-related gene (CRG) -high with upregulated cuproptosis drivers, heightened macrophage/T-cell infiltration, and NF-κB-mediated neuroinflammation, and CRG-low exhibiting disrupted copper homeostasis. Hub genes (CD44, PDE5A, TUBA1A) linked cuproptosis to astrocyte-driven immune interactions, endothelial dysfunction, and neuronal stress. Single-cell analysis localized CD44 to astrocytes interacting with microglia, while PDE5A and TUBA1A correlated with blood-brain barrier leakage and neuronal hyperexcitability. Experimental validation confirmed decreased CD44 and elevated PDE5A/TUBA1A in TLE mice, aligning with seizure severity. Conclusion: This study firstly establishes cuproptosis as a mechanistic bridge between copper dysregulation and TLE pathology, driving neuroinflammation via NF-κB and neuronal-glial dysfunction. The CRG-based subtyping offers novel disease classification, while CD44, PDE5A, and TUBA1A emerge as therapeutic targets to mitigate copper-mediated neurotoxicity. These findings reposition cuproptosis as a key pathway in epilepsy, providing a roadmap for precision therapy in drug-resistant TLE.
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