Cuproptosis-related genes signature and validation of differential expression and the potential targeting drugs in temporal lobe epilepsy

Xiaolin Yang; Xiaoqing Zhang; Kaifeng Shen; Zhongke Wang; Guolong Liu; Kaixuan Huang; Zeng He; Yang Li; Zhi Hou; Shengqing Lv; Chunqing Zhang; Hui Yang; Shiyong Liu; Yanyan Ke

doi:10.3389/fphar.2023.1033859

Cuproptosis-related genes signature and validation of differential expression and the potential targeting drugs in temporal lobe epilepsy

Front Pharmacol. 2023 Jun 26:14:1033859. doi: 10.3389/fphar.2023.1033859. eCollection 2023.

Authors

Xiaolin Yang¹, Xiaoqing Zhang¹, Kaifeng Shen¹, Zhongke Wang², Guolong Liu¹, Kaixuan Huang¹, Zeng He¹, Yang Li¹, Zhi Hou¹, Shengqing Lv¹, Chunqing Zhang^{1

3}, Hui Yang^{1

3}, Shiyong Liu^{1

3}, Yanyan Ke¹

Affiliations

¹ Department of Neurosurgery, Second Affiliated Hospital, Army Medical University, Chongqing, China.
² Department of Neurosurgery, Armed Police Hospital, Chongqing, China.
³ Guangyang Bay Laboratory, Chongqing Institute for Brain and Intelligence, Chongqing, China.

Abstract

Introduction: Temporal lobe epilepsy (TLE) is the most common subtype of epilepsy in adults and is characterized by neuronal loss, gliosis, and sprouting mossy fibers in the hippocampus. But the mechanism underlying neuronal loss has not been fully elucidated. A new programmed cell death, cuproptosis, has recently been discovered; however, its role in TLE is not clear. Methods: We first investigated the copper ion concentration in the hippocampus tissue. Then, using the Sample dataset and E-MTAB-3123 dataset, we analyzed the features of 12 cuproptosis-related genes in TLEs and controls using the bioinformatics tools. Then, the expression of the key cuproptosis genes were confirmed using real-time PCR and immunohistochemical staining (IHC). Finally, the Enrichr database was used to screen the small molecules and drugs targeting key cuproptosis genes in TLE. Results: The Sample dataset displayed four differentially expressed cuproptosis-related genes (DECRGs; LIPT1, GLS, PDHA1, and CDKN2A) while the E-MTAB-3123 dataset revealed seven DECRGs (LIPT1, DLD, FDX1, GLS, PDHB, PDHA1, and DLAT). Remarkably, only LIPT1 was uniformly upregulated in both datasets. Additionally, these DECRGs are implicated in the TCA cycle and pyruvate metabolism-both crucial for cell cuproptosis-as well as various immune cell infiltrations, especially macrophages and T cells, in the TLE hippocampus. Interestingly, DECRGs were linked to most infiltrating immune cells during TLE's acute phase, but this association considerably weakened in the latent phase. In the chronic phase, DECRGs were connected with several T-cell subclasses. Moreover, LIPT1, FDX1, DLD, and PDHB were related to TLE identification. PCR and IHC further confirmed LIPT1 and FDX1's upregulation in TLE compared to controls. Finally, using the Enrichr database, we found that chlorzoxazone and piperlongumine inhibited cell cuproptosis by targeting LIPT1, FDX1, DLD, and PDHB. Conclusion: Our findings suggest that cuproptosis is directly related to TLE. The signature of cuproptosis-related genes presents new clues for exploring the roles of neuronal death in TLE. Furthermore, LIPT1 and FDX1 appear as potential targets of neuronal cuproptosis for controlling TLE's seizures and progression.

Keywords: Fdx1; LIPT1; cuproptosis; diagnostic indicator; immune microenvironment; temporal lobe epilepsy.

Grants and funding

The research received the following funding: National Natural Science Foundation of China (82171448); Natural Science Foundation of Chongqing (2019MSXM099) and Chongqing Technology Innovation and Application Development Special key Project (cstc2019jscx-dxwtBX0010).