Dysregulated Epoxy Fatty Acid Metabolism as a Driver of Pathophysiology: Biosynthesis, Metabolism, and Therapeutic Implications.

Epoxy fatty acids (EpFAs) are lipid mediators with dual physiological roles. They promote protective vascular and inflammatory responses when enzymatically balanced yet may drive pathological dysfunction when metabolic regulation is disrupted. Recent evidence indicates that, their effects are altered under conditions of metabolic stress, oxidative imbalance or prolonged dietary overexposure. Dysregulated cytochrome P450 (CYP) activity or elevated soluble epoxide hydrolase (sEH) expression disrupts the natural epoxide-to-diol balance, enhancing the formation of diol metabolites increasingly linked to cytotoxicity, mitochondrial dysfunction, and tissue injury. Exogenous EpFAs generated during repeated high-temperature frying accumulate in the diet at levels capable of promoting toxic diol formation, particularly from linoleic acid (LA) derived epoxy hydroxy octadecenoic acids (EpHOMEs). These metabolites have been associated with pulmonary injury and immune dysfunction in critical illness. In contrast, omega-3-derived epoxy metabolites demonstrate opposing actions, limiting angiogenesis and tumour dissemination. Together, the contrasting actions of EpFAs reflect a delicately balanced metabolic system in which enzymatic equilibrium determines whether these lipid mediators act as cytoprotective signals or drivers of pathology. Understanding EpFAs biosynthesis, dietary sources, and sEH - dependent bioactivation is important for developing targeted therapeutic strategies and establishing a clear regulatory framework for edible oil safety.