Complement system-mediated immunomodulation in epilepsy: From pathogenesis to therapeutic opportunities

Epilepsy is a prevalent neurological disorder characterized by recurrent seizures and aberrant neuronal hyperexcitability. Although several antiseizure medications are clinically available, current treatments are primarily symptomatic and fail to prevent epileptogenesis or disease progression. Moreover, nearly one-third of patients develop resistance to these drugs. The absence of effective disease-modifying therapies underscores the urgent need to identify novel pathogenic mechanisms and therapeutic targets. As a core component of innate immunity, the complement system has recently emerged as a key regulator of injury and repair processes in the central nervous system. Accumulating preclinical evidence indicates that abnormal complement activation contributes to epileptogenesis. This suggests that complement dysregulation is not merely an epiphenomenon of neuroinflammation but rather a potential driver of seizure development and progression. However, clinical evidence remains limited and heterogeneous, and has not yet been systematically integrated. This review summarizes current preclinical and clinical evidence on complement-mediated mechanisms in epilepsy, with a focus on neuroinflammation, synaptic remodeling, glial proliferation, biomarkers, and therapeutic targets. It also discusses the challenges and opportunities associated with developing complement-based disease-modifying strategies for epilepsy.