Targeting 2-hydroxyglutarate mediates the antidepressant effects of Hericium coralloides polysaccharide in hyperlipidemia-associated depression

Depression, a prevalent emotional disorder, frequently co-occurs with hyperlipidemia. This study investigated the therapeutic effects of Hericium coralloides polysaccharide (HCP) on comorbid hyperlipidemia and depression in mouse models subjected to a high-fat diet (HFD) and chronic unpredictable mild stress (CUMS). The results demonstrated that HFD and CUMS induced blood lipid abnormalities, depressive-like behaviors, increased levels of (S)-2-hydroxyglutarate (2-HG), and hippocampal synaptic damage. Notably, 2-HG acted as a pathogenic hub: it inhibited the brain-derived neurotrophic factor (BDNF)/tropomyosin receptor kinase B (TrkB)/mechanistic target of rapamycin complex 1 (mTORC1) pathway and altered the expression of 5-HT receptors, glycine transporter 2 (GlyT2), and doublecortin-like kinase (Dclk1), thereby aggravating lipid dysregulation and depressive symptoms and reducing synapse numbers and dendritic spine density. HCP regulated the intestinal microbiota and brain metabolites, reducing the levels of Faecalibaculum rodentium, which showed a positive correlation with 2-HG. HCP also lowered blood lipid and 2-HG levels and enhanced synaptic function by activating the BDNF/TrkB/mTORC1 signaling pathway, thereby ameliorating both dyslipidemia and depressive-like behaviors. These findings identify 2-HG as a central mediator linking metabolic and neurological pathologies and show that HCP exerts its therapeutic effects mainly by targeting this novel pathogenic hub.