Bempedoic Acid mitigates BCG-induced depression in mice by modulating TNF-α/NF-κB signaling and restoring brain serotonin contents.

Emerging research implicates systemic inflammation in the disruption of neuroimmune signaling, contributing to the pathogenesis of major depressive disorder. While ATP-citrate lyase (ACLY) is a key lipogenic enzyme that amplifies immune cell-mediated inflammatory responses, bempedoic acid (BA), a recently approved ACLY inhibitor for hypercholesterolemia, has demonstrated significant anti-inflammatory properties. Therefore, we investigated the antidepressant potential of BA in a mouse model of BCG-induced depression, focusing on its interaction with peripheral tumor necrosis factor-alpha (TNF-α) and the downstream modulation of brain NF-κB signaling and serotonin levels. Male Swiss Albino mice were inoculated with BCG to induce systemic inflammation-associated depressive phenotypes. BA was administered alone or with TNF-α inhibitor etanercept. Behavioral assessments included sucrose preference test (SPT), tail suspension test (TST), and locomotor activity (LMA). Levels of TNF-α in the serum, and NF-κB and serotonin contents in the brain were estimated using ELISA and HPLC techniques. BCG administration significantly reduced sucrose preference in SPT and increased immobility in TST, correlating with elevated TNF-α and NF-κB, and reduced serotonin contents. BA treatment significantly reversed these behavioral and biochemical abnormalities, and its combination with etanercept produced synergistic effects, without affecting the LMA. This study provides the first evidence of the antidepressant effect of BA, demonstrating that suppression of peripheral TNF-α by BA leads to downregulation of central NF-κB and restoration of serotonin levels. Further investigations in diverse animal models are warranted to confirm the broad-spectrum efficacy of BA, along with the evaluation of its translational potential for treating depression.