Multi-omics reveals that genes linked to succinylation regulate the onset of epilepsy through metabolic reprogramming

The relationship between succinylation modification and epilepsy is not yet well defined, and the potential mediation of metabolic imbalance in its regulatory pathways requires deeper investigation. This study combines Mendelian randomization (MR) and single-cell transcriptomic techniques to investigate the causal interplay between succinylation-related genes, plasma metabolites, and epilepsy. Specifically, the eQTLGen and plasma metabolite databases are utilized for two-sample MR analysis, which evaluates genetic instrumental variables and quantifies causal effects. The two-step MR approach is applied to identify potential metabolic pathways mediating these genetic effects. This study integrates single-cell data from the temporal lobe of epilepsy patients to delineate cell-type-specific gene expression and regulatory networks. MR analysis identified that elevated expression of the CTBP1 gene significantly increases the risk of epilepsy (OR = 1.052, p = 0.0026). This pathogenic effect is mediated through the dysregulation of eight metabolites: a reduction in six neuroprotective sphingolipids and ceramide (β < 0), coupled with an accumulation of the pro-epileptic metabolite Methylsuccinate (β > 0). Among these, Sphingomyelin (d18:1/21:0, d17:1/22:0, d16:1/23:0) exhibited the highest mediation ratio (25.71%). Single-cell transcriptomics further revealed that CTBP1 is specifically highly expressed in excitatory neurons. In the epileptic temporal lobe, these neurons displayed rewired intercellular communication, primarily characterized by enhanced signaling via the NRG3-ERBB4 axis, alongside alterations in neuroimmune and metabolic pathways. This study provides the first integrated multi-omics evidence that CTBP1 may promote epileptogenesis through metabolic reprogramming and neuronal heterogeneity regulation, suggesting a potential role for CTBP1-mediated metabolic reprogramming in temporal lobe excitatory neurons in the disorder's pathology.