The role of arachidonic acid metabolites in major depressive disorder: mechanisms and therapeutic implications

Metab Brain Dis. 2025 Nov 6;40(8):311. doi: 10.1007/s11011-025-01733-4.

ABSTRACT

Arachidonic acid (AA) is an important omega-6 polyunsaturated fatty acid (PUFA) stored in esterified form within cell membrane phospholipids, and it is widely present in various cell types. The esterified AA on the inner surface of the cell membrane is primarily hydrolyzed by phospholipase A2 (PLA₂) into its free form. Subsequently, it is metabolized by cyclooxygenase (COXs), lipoxygenase (LOXs), and cytochrome P450 (CYP450) enzymes. The metabolites of AA include a range of bioactive mediators such as prostaglandins (PGs), epoxyeicosatrienoic acids (EETs), hydroxyeicosatetraenoic acids (HETEs), leukotrienes (LTs) and lipoxins (LXs). These metabolites play critical and diverse roles in cellular physiology and are implicated in the pathogenesis of major depressive disorder. This review delves into the molecular mechanisms by which arachidonic acid and its metabolites contribute to the development of major depressive disorder, providing new perspectives for the development of novel antidepressant therapies.

PMID:41196452 | DOI:10.1007/s11011-025-01733-4