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已发表论文
铜死亡与颞叶癫痫免疫微环境的相互作用：关键分子特征及治疗靶点的鉴定
Authors Li W, Guo Q, Li X, Huang L , Liu H, Liu S
Received 19 August 2025
Accepted for publication 27 October 2025
Published 5 December 2025 Volume 2025:18 Pages 17089—17112
DOI https://doi.org/10.2147/JIR.S561184
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Dr Adam Bachstetter
Weida Li,1 Qi Guo,1 Xinxin Li,1 Limin Huang,1 Haiyan Liu,2 Songyan Liu1
1Department of Neurology, China-Japan Union Hospital, Jilin University, Changchun, People’s Republic of China; 2The Key Laboratory of Pathobiology Ministry of Education, Department of Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, 130061, People’s Republic of China
Correspondence: Haiyan Liu, Email haiyan@jlu.edu.cn Songyan Liu, Email liu_sy@jlu.edu.cn
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.
Keywords: temporal lobe epilepsy, cuproptosis-related gene, cuproptosis
1Department of Neurology, China-Japan Union Hospital, Jilin University, Changchun, People’s Republic of China; 2The Key Laboratory of Pathobiology Ministry of Education, Department of Anatomy, College of Basic Medical Sciences, Jilin University, Changchun, 130061, People’s Republic of China
Correspondence: Haiyan Liu, Email haiyan@jlu.edu.cn Songyan Liu, Email liu_sy@jlu.edu.cn
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.
Keywords: temporal lobe epilepsy, cuproptosis-related gene, cuproptosis