Canonical and non-canonical STAT3 pathways in epilepsy: Mechanistic insights and translational challenges

Epileptogenesis is a multifactorial cascade involving neuroinflammation, glial activation, neuronal hyperexcitability, abnormal synaptic plasticity, and cell death. Understanding the epileptogenic changes is critical for improving therapeutic outcomes. Despite extensive knowledge of inflammatory pathways in epilepsy, the role of signal transducer and activator of transcription 3 (STAT3) remains underexplored. This review synthesizes the current evidence on classical and alternative STAT3 signalling mechanisms in epilepsy. Classical cytokine-driven Janus Kinase (JAK)/STAT3 signalling promotes neuroinflammation and gliosis in epilepsy, whereas non-classical STAT3 functions modulate mitochondrial, epigenetic, and ion-channel/neurotransmitter-receptor homeostasis. Mechanistically, STAT3 promotes neuronal hyperexcitability by repressing gamma-aminobutyric acid (GABA_A) receptor α1 subunit expression, thereby disrupting the inhibitory neurotransmission. Additionally, STAT3 links neuroinflammation to ferroptosis via astrocyte chemokine signalling and crosstalk with the mechanistic target of rapamycin (mTOR), Rho-associated coiled-coil containing protein kinase 2 (ROCK2), and nuclear factor erythroid 2-related factor 2 (Nrf2) pathways. Preclinical studies have demonstrated that pharmacological inhibitors, cell-specific genetic deletion, and RNA-based silencing of STAT3 attenuate seizures and preserve GABAergic interneurons. However, clinical translation is constrained by challenges in pathway specificity, blood-brain barrier penetration, and selective modulation of pathological and physiological functions. Altogether, the current review identifies STAT3 as a critical integrator of inflammatory, metabolic, and excitability-related signalling networks that drive epileptogenic remodelling and delineates future directions for mechanism-driven, precision-based, and combinatorial interventions to harness STAT3-directed therapies in epilepsy.