Brain Research Bulletin NF-κB as a context-dependent inflammatory regulator of glial programs in epilepsy

Neuroinflammation is increasingly recognized as an important contributor to epileptogenesis and seizure recurrence, with microglia and astrocytes serving as major regulators of the inflammatory microenvironment. Among the pathways implicated in glia-mediated inflammation, nuclear factor kappa B (NF-κB) occupies a central position by integrating danger signals, metabolic stress, and activity-dependent inputs into inflammatory transcriptional responses. However, current evidence indicates that NF-κB should not be viewed as a uniformly pro-inflammatory pathway or as a single therapeutic switch. Rather, its effects vary according to cell type, upstream signaling context, activation dynamics, and disease stage. In this review, we synthesize evidence on NF-κB-associated signaling in epilepsy across damage-sensing, amplification, metabolic stress, purinergic, and ncRNA-associated modules. We distinguish relatively well-supported pro-inflammatory and neurotoxic inflammatory outputs from more provisional interpretations regarding repair-compatible glial responses. We also evaluate therapeutic strategies that directly or indirectly target NF-κB-related signaling and discuss the limitations of inferring causal NF-κB involvement from multi-target compounds or downstream inflammatory markers. Collectively, this review presents NF-κB as a context-dependent regulator of glia-associated inflammatory outputs in epilepsy and proposes module-specific modulation as a working framework for organizing current evidence and guiding future experimental validation.