Lipoxygenase (LOX) signaling in epilepsy: Pathophysiology and therapeutic prospects.

Epilepsy is a devastating neurological disorder affecting about 1-2% of the global population and is characterized by recurrent, unprovoked seizures that can severely impair quality of life. Despite the availability of antiseizure medications, nearly one-third of individuals with epilepsy continue to experience drug-resistant seizures, underscoring the need for novel therapeutic strategies. Growing evidence supports neuroinflammation as a key driver of epileptogenesis following brain insults. At the biochemical level, this neuroinflammatory response is largely propagated through the classic arachidonic acid metabolic cascade. Within this pathway, lipoxygenase (LOX) enzymes play a pivotal role in mediating oxidative stress, lipid peroxidation, and pro-inflammatory signaling through the generation of bioactive lipid metabolites. Dysregulation of LOX activity contributes to epileptogenic processes, such as blood-brain barrier disruption, glial activation, cytokine release, immune-cell infiltration, neuronal hyperexcitability, and neuronal death. Emerging evidence indicates that LOX pathways, particularly those mediated by 5-LOX and 12/15-LOX, play a major role in the pathophysiology of epileptic seizures and may also contribute to neuropsychiatric comorbidities that substantially reduce quality of life. In this review, we discuss the therapeutic potential of targeting 5-LOX and 12/15-LOX for seizure disorders, integrating current preclinical evidence and mechanistic insights to advance the development of novel, safer, and more effective therapies for epilepsy and its associated neurological comorbidities. Together, these perspectives highlight promising avenues for future research and therapeutic innovation.