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

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.

Identification of cuproptosis-related gene clusters and immune cell infiltration in major burns based on machine learning models and experimental validation

“…Cuproptosis is a Cu-dependent form of cell death associated with mitochondrial metabolism. Multiple studies have shown a close association between cardioproptosis and the occurrence and progression of various diseases, such as atherosclerosis, pulmonary hypertension, epilepsy, and tumors ( 31 – 33 ). Additionally, patients with sepsis may have elevated levels of Cu ions in their body.…”

The roles of essential trace elements in T cell biology

“… 87 In Temporal lobe epilepsy, upregulated CRGs may promote peripheral CD4 + and CD8 + T cell infiltration into epileptic focus, which increases seizure frequency. 88 In patients with pancreatic adenocarcinoma, CRGs may drive the infiltration of antitumor components, such as activated CD4 + and CD8 + T cells, which are associated with longer survival. 89 Further, copper‐coated nanomaterial sticking to T cell membrane could target the triple‐negative tumour cells to promote cuproptosis, offering promising applications in tumour immunotherapy.…”

“…In addition, cuproptosis‐related genes (CRGs) may influence T cell exhaustion phenotype and serve as effective prognostic indicators for lung adenocarcinoma 87 . In Temporal lobe epilepsy, upregulated CRGs may promote peripheral CD4 + and CD8 + T cell infiltration into epileptic focus, which increases seizure frequency 88 . In patients with pancreatic adenocarcinoma, CRGs may drive the infiltration of antitumor components, such as activated CD4 + and CD8 + T cells, which are associated with longer survival 89 .…”

The Molecular Mechanisms of Cuproptosis and Small-Molecule Drug Design in Diabetes Mellitus

“…It may be suggested, then, that FDX1 is associated with the regulatory pathway of DEX [ 85 ]. Yang X. et al used the Enrichr database to analyze small molecules and drugs targeting the key cuproptosis protein in temporal lobe epilepsy (TLE), and found that chlorzoxazone and piperlongumine were the most likely to target cuproptosis genes and thus inhibit cuproptosis [ 86 ]. In addition, Jinke Huang.…”