Molecular fingerprints of drug-resistant epilepsy identified through liquid biopsy profiling

Nearly one-third of individuals with epilepsy exhibit resistance to antiseizure medications (ASMs). Proposed mechanisms underlying drug resistance include metabolic impairments within brain tissue, maladaptive axonal sprouting with synaptic remodeling, and mutations that affect ion channels or neurotransmitter receptors. These pathophysiological alterations give rise to molecular changes in the cerebrospinal fluid (CSF) and peripheral circulation. Here, we summarize emerging molecular biomarkers of drug-resistant epilepsy that are detectable in CSF, blood, and saliva. Growing evidence highlights both generic biomarkers, such as HMGB1, tau, YKL-40, acetoacetate, IL-1β, IL-6, IL-7, CCL11, and miR-146a, and epilepsy-type-specific markers, including allopregnanolone, progesterone, and melatonin. Further research and validation of molecular fingerprints that distinguish ASM-responsive from ASM-resistant epilepsy variants hold significant promise for improving differential diagnosis and enabling more effective therapeutic strategies. [Abstract copyright: Copyright © 2026 The Author(s). Published by Elsevier Ltd.. All rights reserved.]