Association of environmental xylene exposure with diabetic kidney disease: a cross-sectional analysis and multi-omics evaluation of immune microenvironment mechanisms.

Diabetic kidney disease (DKD) progression is driven by residual inflammation, potentially exacerbated by volatile organic compounds (VOCs). However, the impact of xylene exposure on the DKD immune microenvironment remains unclear. We evaluated the association between urinary VOC metabolites and DKD prevalence using NHANES data. Network toxicology and bulk transcriptomics (GSE142025) were integrated to identify core targets and profile immune infiltration. Single-cell RNA sequencing (GSE209781) validated macrophage heterogeneity and hub gene dynamics, and molecular docking assessed xylene-receptor binding affinities. Elevated urinary xylene metabolite (DPMA) correlated with increased DKD odds (OR = 4.03, 95% CI: 1.80-9.00). Multi-omics identified ITGAM, CSF1R, and CTSS as primary hub genes enriched in immune pathways. Both bulk and single-cell RNA sequencing analyses revealed that DKD tissues exhibited M2-like macrophage enrichment and an expansion of fibrotic SPP1+ subsets. This altered microenvironment positively correlated with hub gene upregulation along the macrophage developmental trajectory. Molecular docking suggested potential binding between xylene isomers and these receptors (binding free energies: -4.7 to -5.9 kcal/mol). Environmental xylene exposure is independently associated with higher DKD odds. These findings generate the hypothesis that xylene may interact with specific macrophage receptors (ITGAM, CSF1R, CTSS), potentially promoting M2-like macrophage polarization and fibrotic remodeling. This putative environmental-immunological axis warrants further experimental validation.