STAT3 signaling is associated with neuroimmune dysregulation in a Dravet syndrome model and pediatric drug-resistant epilepsy
Year: 2026
Type: article
Study design: Observational Study
Abstract: Background Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy, mainly caused by SCN1A gene mutations. Its core characteristics are heat sensitivity and refractoriness, and immunoinflammatory factors can participate in the occurrence and development of the disease. At present, the regulatory role of immune inflammation activation in DS has been confirmed, but the specific molecular core connecting systemic inflammation and central nervous system signals and its translational relevance to broader pediatric drug-resistant epilepsy (DRE) remains unclear. Methods We conducted a multi-level integrative analysis combining transcriptomic mining of the GEO database to identify the Stat3 hub, with clinical validation in a real-world pediatric cohort from our hospital, comparing DRE (including DS) and self-limited epilepsy with centrotemporal spikes (SeLECTS), to assess the clinical relevance of systemic inflammatory indices (NLR, SII, CRP). Findings were mechanistically verified in Scn1a +/− mice via qRT-PCR, Western blotting, and immunofluorescence, using robust linear models to confirm central-peripheral inflammation correlations. Results Transcriptomic profiling of Scn1a +/− mice revealed a distinct inflammatory landscape (PC1 = 86%) dominated by JAK-STAT signaling, with Stat3 identified as a consensus hub. Clinically, this systemic inflammatory signature was observed in our pediatric cohort ( n = 140). Baseline inflammatory indices (NLR, SII, CRP) were significantly elevated in patients with drug-resistant epilepsy compared to those with SeLECTS ( p < 0.001). Multivariable analysis further identified CRP as an independent factor closely associated with progression to drug resistance (OR = 2.79, p = 0.025). In vivo validation confirmed p-STAT3 hyperactivation in hippocampal gliosis ( p < 0.0001), which exhibited robust linear correlations with peripheral markers ( r ≥ 0.94, p < 0.001). Conclusion This study identifies systemic and neuroinflammatory changes in DS associated with increased STAT3 signaling and this inflammatory signature is also observed in the broader pediatric DRE population. By bridging verified molecular mechanisms with real-world clinical data from our pediatric cohort, we suggest peripheral indices (NLR, SII, CRP) that may serve as accessible clinical indicators of disease severity in pediatric DRE. Pending functional validation, these findings identify STAT3 as a pathway of interest and a potential therapeutic candidate, supporting the development of adjunctive anti-inflammatory therapies targeting neuroimmune cascades for DS and broader refractory epilepsies.
Source: Frontiers in Neuroscience
Authors: Qi Zhang, Ji-Chen Wang, Hai-Qing Zhao, Jia Wang, Bing-Jie Xu, Li-Ping Zou
Institutions: Chinese PLA General Hospital, Nankai University
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
OpenAlex ID: W7154024455