Modulating fatty acid signaling to restore allopregnanolone balance: A novel strategy for anxiety disorders

Anxiety disorders, affecting up to 28 % of individuals globally, remain poorly treated, necessitating novel therapeutic targets. Here, we identify Elovl6, a key fatty acid elongase enriched in the human cerebral cortex, as a critical regulator of anxiety-like behaviors. Chronic stress downregulated Elovl6 in the prefrontal cortex (PFC), while Elovl6 knockout (KO) mice exhibited heightened anxiety-like behaviors, including reduced open-arm exploration in the elevated plus maze, increased compulsive grooming, and impaired nest-building, without affecting depression-related phenotypes. Mechanistically, Elovl6 deficiency disrupted brain lipid homeostasis, increasing palmitic acid (PA, C16:0) while decreasing oleic acid (OA, C18:1) and linoleic acid (LA, C18:2), leading to suppressed PPARα expression in astrocytes and reduced allopregnanolone (Allo) levels. Unsaturated fatty acids (OA/LA) or the PPARα agonist GW7647 reversed these deficits, restoring Allo production and alleviating anxiety-like behaviors in Elovl6-KO mice. Our findings reveal a novel Elovl6-fatty acid-PPARα-Allo axis in anxiety pathophysiology and propose lipid metabolism modulation as a promising therapeutic strategy.