Mitochondria-related HSDL2 is a potential biomarker in temporal lobe epilepsy by modulating astrocytic lipid metabolism.

Temporal lobe epilepsy (TLE) is the most prevalent type of focal epilepsy in adults. While comprehensive bioinformatics analyses have facilitated the identification of novel biomarkers in animal models, similar efforts are limited for TLE patients. In the current study, a comprehensive analysis using human transcriptomics datasets GSE205661, GSE190451, and GSE186334 was conducted to reveal differentially expressed genes related to mitochondria (Mito-DEGs). Protein-protein interaction (PPI) network and Least Absolute Shrinkage and Selection Operator (LASSO) regression analyses were performed to identify hub genes. Additional GSE127871 and GSE255223 were utilized to establish the association with hippocampal sclerosis (HS) and seizure frequency, respectively. Single-cell RNA analysis, functional investigation, and clinical verification were conducted. Herein, we reported that the Mito-DEGs in human TLE were significantly enriched in metabolic processes. Through PPI and LASSO analysis, HSDL2 was identified as the hub gene, of which diagnostic potential was further confirmed using independent datasets, animal models, and clinical validation. Subsequent single-cell and functional analyses revealed that HSDL2 expression was enriched and upregulated in response to excessive lipid accumulation in astrocytes. Additionally, the diagnostic efficiency of blood HSDL2 was verified in Qilu cohort. Together, our findings highlight the translational potential of HSDL2 as a biomarker and provide a novel therapeutic perspective for human TLE.