Authors
Chuantao Fang, Guilin Meng, Lin Yang, Lijun Wang, Yanfeng Tan, Jingjing Guo, Ying Shi, Xianming Liu, Rui Zhao, Min Zhang, Lei An, Fang Yuan, Dashi Qi
Published in
Molecular psychiatry. Jul 11, 2026. Epub Jul 11, 2026.
Abstract
Focal cortical dysplasias (FCDs) are a major cause of drug-resistant epilepsy, yet their molecular and pathological complexity has limited the development of effective antiseizure medications. Here, we performed single-nucleus RNA sequencing on 49 human neocortical specimens spanning FCDI-III. We identified prominent transcriptional alterations in non-neuronal populations, particularly astrocytes and vascular cells, with signatures suggestive of endothelial and smooth muscle cell dysfunction. In contrast, neuronal populations exhibited additional subtype-specific heterogeneity. Notably, vascular-associated signatures were consistently observed across FCD subtypes, suggesting a convergent feature of diseased cortex. To systematically explore candidate interventions, we integrated cell-type-resolved transcriptional signatures with the Connectivity Map to prioritize compounds from ~40,000 perturbagens. This analysis yielded 20 candidates, among which four compounds (Betamethasone, Lodamin, Valproxam, and Licochalcone A) reduced seizure-like activity in vivo, as assessed by behavioral assays and local field potential recordings. These effects were further evaluated in an mTOR-driven FCD model. Collectively, our findings establish a transcriptome-guided framework for linking multicellular disease signatures to candidate therapeutic strategies in refractory epilepsy.
PMID:
42436259
Bibliographic data and abstract were imported from PubMed on 12 Jul 2026.
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