Putative Transcriptomic Endotypes Reveal Neuronal, Immune, and Metabolic Heterogeneity in Temporal Lobe Epilepsy with...

Temporal lobe epilepsy with hippocampal sclerosis (TLE-HS) is a biologically heterogeneous disorder in which neuronal loss, gliosis, neuroinflammation, and metabolic stress may coexist but are unlikely to be uniformly represented across all patients. To investigate this heterogeneity at the molecular level, we analysed publicly available hippocampal transcriptomic data from individuals with TLE-HS. Our analyses identified three transcriptomically defined putative endotypes within this shared neuropathological diagnosis. These states were associated with distinct molecular programs, including a neuronal/synaptic signalling-dominant profile, an immune- and glia-associated inflammatory state marked by cytokine and complement pathway activity, and a metabolically shifted state characterised by oxidative phosphorylation, reactive oxygen species signalling, and stress-response pathways. Cell-type-associated transcriptional signatures analysis and co-expression network organisation further characterised these transcriptomic endotypes, indicating that glial activation, inflammatory signalling, and mitochondrial/metabolic remodelling are differentially weighted across TLE-HS rather than uniformly present. These findings suggest that TLE-HS comprises partially distinct molecular contexts that may converge on a common histopathological endpoint. By characterising transcriptomically defined states within TLE-HS, this study highlights molecular heterogeneity within a shared histopathological diagnosis.