Discovering molecular drivers of human epileptogenesis through integrative multi-omics profiling

Epilepsy is a neurological disorder affecting millions worldwide, with drug-resistant epilepsy posing a major treatment challenge. Despite extensive research, the molecular mechanisms underlying epileptogenesis remain incompletely understood. To identify novel biomarkers and therapeutic targets, an integrated multi-omics approach was employed, analyzing Data-Independent Acquisition (DIA) and Parallel Reaction Monitoring (PRM) proteomics, bulk RNA-seq, and single-nucleus RNA-seq (snRNA-seq) data. Human brain tissues from epilepsy surgeries were divided into three groups: the seizure onset zone (Core, C), marginal excision tissue (Border, B), and non-epileptic controls (N). Differentially expressed proteins (DEPs) and genes (DEGs) were identified across groups. Key molecules, OXR1, GLRX, CCK, and PLCB1 emerged as potential drivers of epilepsy progression, offering insights into epileptic discharge mechanisms and disease development. These findings highlight promising targets for future therapies. CLINICAL PERSPECTIVES: Epilepsy, particularly drug-resistant forms, poses significant treatment challenges due to limited understanding of its molecular mechanisms. This study was undertaken to identify key biomarkers and therapeutic targets through integrative multi-omics profiling of human epileptic tissues, addressing gaps left by animal models and inconsistent prior research. Analyzing surgical samples from the seizure onset zone (Core), adjacent border tissue (Border), and non-epileptic controls, the study revealed consistent alterations in proteins (e.g., OXR1, GLRX, CCK, PLCB1) and genes across these regions. These molecules are implicated in oxidative stress, synaptic signaling, and neuronal excitability, offering insights into epileptogenesis. The findings highlight potential targets for novel therapies, particularly for drug-resistant epilepsy, and underscore the importance of glial and neuronal interactions in disease progression. By bridging proteomic and transcriptomic data, this research advances precision medicine approaches, paving the way for improved diagnostics and targeted treatments to mitigate seizure burden and enhance patient outcomes.