Identification and validation of senescence-associated secretory phenotype-related biomarkers in epilepsy

Epilepsy is increasingly linked to cellular senescence and the senescence-associated secretory phenotype (SASP), which propagates sterile neuroinflammation and tissue remodeling. However, the specific SASP-related molecular signatures driving epileptogenesis remain poorly characterized. Integrating human cortical transcriptomic profiles (GSE256068) with a curated SASP gene set, we identified 22 differentially expressed candidates. Machine-learning feature selection (LASSO and SVM-RFE) converged on a robust five-biomarker panel (IGFBP4, SERPINE1, CCL2, C3, and SPX), which demonstrated consistent differential expression in an independent, cross-regional hippocampal dataset (GSE134697). A diagnostic nomogram integrating these markers achieved excellent discrimination and clinical net benefit. Functional enrichment linked this panel to oxidative phosphorylation and translational control. Crucially, the up-regulation of SERPINE1 and CCL2 highlights a neurochemical mechanism involving extracellular matrix remodeling and inferred neuroimmune microenvironment shifts. In silico regulatory network analysis further predicted upstream transcription factors governing this axis. Finally, RT-qPCR validation in the peripheral blood of a kainic acid-induced epilepsy mouse model confirmed the significant dysregulation of four key biomarkers (IGFBP4, SERPINE1, CCL2, and C3). Collectively, our study defines a highly accurate SASP-associated biomarker panel and provides profound neurochemical insights into senescence-linked inflammatory networks, offering novel targets for the diagnosis and management of epilepsy.