Urinary Volatile Organic Compound Metabolites and Depressive Symptoms Among U.S. Adults With Cardiovascular-Kidney-Metabolic Syndrome Stages 0-3: NHANES-Based Associations and In Silico Multi-Omics Insights.

BACKGROUND: Depression is a major global public health burden, and environmental pollutants are increasingly associated with depressive symptoms. Volatile organic compounds (VOCs) are ubiquitous environmental contaminants with known neurotoxic potential; however, their associations with depressive symptoms, particularly in metabolically vulnerable populations such as those with cardiovascular-kidney-metabolic (CKM) syndrome, remain insufficiently characterized. METHODS: We conducted a population-based study of adults with CKM stages 0-3 using data from NHANES 2011-2018, assessing associations between urinary levels of 16 VOC metabolites and PHQ-9-defined depressive symptoms using multivariable logistic regression, dose-response modeling, and mixture analyses. Machine learning identified key exposures, network toxicology revealed shared molecular targets and pathways, single-cell RNA sequencing characterized cell-type-specific expression and functional states, and molecular docking assessed interactions between prioritized mVOCs and protein targets. RESULTS: Higher urinary levels of CYMA, MHBMA3, and HMPMA were significantly associated with increased odds of depressive symptoms after full adjustment, with approximately linear or nonlinear dose-response relationships. Mixture analysis indicated that these metabolites were the main contributors to the joint VOC exposure effect. Network toxicology identified enrichment of depression-related targets in neuronal signaling, synaptic transmission, and immune regulation pathways. Exploratory analysis of public scRNA-seq datasets suggested higher PIK3R1 expression in PBMC CD8+ T cells from depression-related samples and indicated altered immune-related transcriptional programs. Molecular docking suggested plausible binding interactions between the prioritized VOCs and PIK3R1. CONCLUSIONS: Higher urinary VOC metabolite levels were associated with higher odds of PHQ-9-defined depressive symptoms among adults with CKM stages 0-3.In silico multi-omics analyses suggested potential involvement of PI3K/AKT-related neuroimmune pathways.