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This study investigates the potential involvement of 4\u2010hydroxybenzyl alcohol (4\u2010HBA), a bioactive molecule known for its neuroprotective and anti\u2010inflammatory effects, in the pathophysiology of hyperlipidemia\u2010associated depression. High\u2010fat diet (HFD)\u2010fed mice develop concurrent hyperlipidemia and depression\u2010like behaviors, with 4\u2010HBA identified as a key modulated brain metabolite in fecal microbiota transplantation recipients. In HFD\u2010fed mice, 4\u2010HBA treatment simultaneously improves lipid metabolism and significantly alleviates depression\u2010like behaviors, accompanied by suppression of the nuclear factor \u03baB (NF\u2010\u03baB) signaling pathway in the brain. In LPS\u2010stimulated BV2 cells, 4\u2010HBA inhibits NF\u2010\u03baB activation through NF\u2010\u03baB inhibitor interacting Ras\u2010like 2 (NKIRAS2), thereby coordinating the downregulation of inflammatory responses. Conditioned medium from 4\u2010HBA\u2010treated BV2 cells enhances neuronal viability and reduces inflammatory responses in HT22 neurons in co\u2010culture. Importantly, silencing\n                    <jats:italic>Nkiras2<\/jats:italic>\n                    in BV2 cells and organotypic brain slice cultures negated the anti\u2010inflammatory and neuroprotective actions of 4\u2010HBA. These findings demonstrate that the NKIRAS2\/NF\u2010\u03baB pathway is a molecular mediator underlying the biological effects of 4\u2010HBA. These findings position 4\u2010HBA as a dual\u2010action metabolite capable of concurrently mitigating metabolic and psychiatric manifestations through neuroinflammatory regulation.\n                  <\/jats:p>","DOI":"10.1002\/advs.202517873","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T15:03:43Z","timestamp":1773068623000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["4\u2010Hydroxybenzyl Alcohol Mitigates Hyperlipidemia\u2010Associated Depression by Inhibiting Neuroinflammation via the NKIRAS2\/NF\u2010\u03baB Pathway"],"prefix":"10.1002","volume":"13","author":[{"given":"Ying","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Life Sciences Jilin University  Changchun China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Teng","sequence":"additional","affiliation":[{"name":"School of Life Sciences Jilin University  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