Translational Potential of the Epoxyeicosatrienoic Acid Pathway in Neurological Disorders

Neurological disorders represent a leading cause of global disability and mortality. Given that current single-target therapies often fail to halt disease progression or cross the blood-brain barrier (BBB), novel therapeutic strategies are urgently needed. Endogenous lipid networks offer promising targets. They are major structural components of the central nervous system (CNS) that provide multi-target neuroprotection essential for homeostasis and can bypass BBB restrictions naturally or via brain-penetrant small-molecule modulation. Among these lipids, arachidonic acid (AA) accounts for approximately 20% of total neuronal fatty acids. Upon cellular activation, while the cyclooxygenases (COXs) and lipoxygenases (LOXs) pathways yield pro-inflammatory mediators targeted by classic drugs, the cytochrome P450 (CYP450) cascade generates protective epoxyeicosatrienoic acids (EETs), which serve as fundamental regulators of systemic and neural homeostasis. Within the CNS, EETs act as crucial protectors of the neurovascular unit (NVU) by regulating cerebral blood flow (CBF), maintaining BBB integrity, and promoting angiogenesis. Furthermore, they actively mitigate neuroinflammation by suppressing microglial activation, reducing oxidative stress, and inhibiting neuronal apoptosis. Through these multifaceted mechanisms, alongside the enhancement of neurogenesis and synaptic plasticity, EETs effectively protect the brain against ischemic stroke, neurodegenerative diseases, and other neurological insults. Consequently, this article comprehensively reviews the physiological roles, underlying mechanisms, and regulatory factors of EETs in the nervous system. Ultimately, by highlighting the translational potential of targeted soluble epoxide hydrolase (sEH) inhibition and EET elevation, this review aims to pave the way for innovative neuroprotective therapies.