4‐Hydroxybenzyl Alcohol Mitigates Hyperlipidemia‐Associated Depression by Inhibiting Neuroinflammation via the NKIRAS2/NF‐κB Pathway

ABSTRACT Epidemiological data link hyperlipidemia to increased depression susceptibility. This study investigates the potential involvement of 4‐hydroxybenzyl alcohol (4‐HBA), a bioactive molecule known for its neuroprotective and anti‐inflammatory effects, in the pathophysiology of hyperlipidemia‐associated depression. High‐fat diet (HFD)‐fed mice develop concurrent hyperlipidemia and depression‐like behaviors, with 4‐HBA identified as a key modulated brain metabolite in fecal microbiota transplantation recipients. In HFD‐fed mice, 4‐HBA treatment simultaneously improves lipid metabolism and significantly alleviates depression‐like behaviors, accompanied by suppression of the nuclear factor κB (NF‐κB) signaling pathway in the brain. In LPS‐stimulated BV2 cells, 4‐HBA inhibits NF‐κB activation through NF‐κB inhibitor interacting Ras‐like 2 (NKIRAS2), thereby coordinating the downregulation of inflammatory responses. Conditioned medium from 4‐HBA‐treated BV2 cells enhances neuronal viability and reduces inflammatory responses in HT22 neurons in co‐culture. Importantly, silencing Nkiras2 in BV2 cells and organotypic brain slice cultures negated the anti‐inflammatory and neuroprotective actions of 4‐HBA. These findings demonstrate that the NKIRAS2/NF‐κB pathway is a molecular mediator underlying the biological effects of 4‐HBA. These findings position 4‐HBA as a dual‐action metabolite capable of concurrently mitigating metabolic and psychiatric manifestations through neuroinflammatory regulation.