Urinary ubiquitin-specific protease 2 (USP2) as a diagnostic biomarker for chronic kidney disease: an integrated multi-omics and network analysis

Chronic kidney disease (CKD) is associated with progressive metabolic and molecular dysregulation, yet reliable noninvasive biomarkers remain limited. Ubiquitin-specific protease 2 (USP2) regulates transforming growth factor-β signaling and ferroptosis through lactylation-dependent deubiquitinase activity, but its clinical relevance in CKD remains unclear. We enrolled 25 patients with CKD and 10 healthy controls and measured urinary USP2 levels using enzyme-linked immunosorbent assay. Untargeted urine and serum metabolomics and plasma proteomics were integrated with weighted gene co-expression network analysis, mediation analysis, and pathway enrichment. Urinary USP2 was significantly higher in patients with CKD than in healthy controls and remained independently associated with CKD after adjustment for age and sex. USP2 achieved an AUC of 0.936, and the USP2 + Age + Sex model achieved an AUC of 0.972. Decision curve analysis supported the clinical utility of USP2-containing models. FDR-adjusted multi-omics analyses identified urinary and serum metabolite modules and plasma protein modules associated with USP2 and CKD. Mediation analysis suggested that selected urinary and serum metabolites may link USP2-related molecular alterations with CKD. Sensitivity analyses in age-matched and early-stage CKD subsets further supported the diagnostic performance of USP2 and its comparison with kidney injury molecule 1. These findings support urinary USP2 as a promising noninvasive biomarker for CKD and highlight USP2-associated metabolic and proteomic networks that warrant validation in larger cohorts.