Systems Biology of Mesial Temporal Lobe Epilepsy and Role of Iron-Related Gene Expression in Its Pathophysiology

Mesial temporal lobe epilepsy (MTLE) is the most common form of drug-resistant epilepsy in adults, yet its molecular pathogenesis remains elusive. While iron dysregulation has been implicated in MTLE, transcriptome-level regulation of iron-related genes in MTLE brain, including regional, subcellular, and pathology-specific patterns, remains largely unexplored. We analyzed publicly available nuclear and cytoplasmic RNA-sequencing data from hippocampal and cortical tissues of patients with MTLE with and without hippocampal sclerosis and controls. We identified differential expression among 562 curated iron-related genes, which constituted 1.46-2.95% of all differentially expressed genes across regions and compartments. These genes showed region- and compartment-specific expression profiles, with recurrent upregulation of <i>CH25H</i>, <i>TAL1</i>, <i>BTG2</i>, <i>TNF</i>, and <i>PTGIS</i> and consistent downregulation of <i>OGFOD3</i>. Protein-protein interaction and hub gene network analysis identified SLC40A1, CH25H, HBB, PTGIS, and CYP2C19 as central hubs linking iron transport, lipid metabolism, oxidative stress, and neuroprotection. Upstream regulatory analysis revealed enrichment of seizure-responsive immediate early genes (<i>EGR2</i>, <i>ATF3</i>, <i>JUN</i>) and neurogenic transcription factors (<i>NEUROD1</i>, <i>ASCL1</i>), with the former upregulated and the latter downregulated, indicating seizure-driven transcriptional reprogramming. Our analyses suggest potential regulatory links connecting iron homeostasis with apoptosis, osmotic balance, cholesterol metabolism, and pH/CO₂ buffering. Exploratory analysis showed a negative association between several iron-related genes, including <i>CYP26B1</i>, and seizure frequency in MTLE. Collectively, these findings reveal complex transcriptional programs governing iron dysregulation in MTLE. The results underscored coordinated regulation of inflammatory and metabolic pathways converging on iron homeostasis and neuronal stress responses in MTLE pathophysiology, providing a systems-level framework for potential prognosis and therapeutic targeting.