Bempedoic acid attenuates glial lipid droplet accumulation and inflammatory responses and alleviates chronic social defeat stress-induced depressive-like behaviors in mice.

Depression is a common and disabling psychiatric disorder, and chronic psychosocial stress is an important risk factor for stress-related depressive phenotypes. Neuroinflammation and glial changes have been implicated in chronic stress, but whether lipid droplets accumulate in specific brain cell types after stress remains unclear. Bempedoic acid (BPA) is an orally available ATP-citrate lyase inhibitor used for lipid lowering and has anti-inflammatory effects in preclinical studies. Here, male C57BL/6J mice were exposed to 10 days of chronic social defeat stress (CSDS) and treated orally with BPA (30 mg/kg/day). CSDS induced anxiety- and depressive-like behaviors without affecting general locomotor activity. These behavioral changes were accompanied by inflammatory gene changes, altered microglial morphology, reduced hippocampal PSD95 abundance, increased PSD95-positive material within Iba1-positive microglia, and increased microglial lipid droplet accumulation. Lipid droplets were also increased in GFAP-positive astrocytes, whereas no clear change was detected in NeuN-positive neurons. BPA improved the behavioral abnormalities and attenuated microglial morphological changes, PSD95-related changes, glial lipid droplet accumulation, and inflammatory responses. Whole-brain RNA sequencing and quantitative PCR further showed changes in cytokine- and chemokine-related pathways after BPA treatment. These findings support further evaluation of BPA as a drug-repurposing candidate for stress-related depression.