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

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.