Plasma proteomics identifies an endoplasmic reticulum stress-associated molecular signature across cardiovascular-kidney-metabolic syndrome stages

Cardiovascular-kidney-metabolic (CKM) syndrome is a clinical framework driven by interconnected inflammatory, fibrotic, and metabolic mechanisms, although the molecular pathways underlying disease progression remain poorly defined. In this discovery-phase study, we performed unbiased high-throughput plasma proteomic profiling using the SomaScan v5.0 platform (3011 analytes) in 47 CKM participants. Differential protein expression across CKM stages and clinicoproteomic correlations were performed to identify molecular patterns associated with disease progression. A total of 327 proteins showed nominal stage-associated differences at uncorrected p < 0.05, with 147 showing progressive increases and 60 progressive decreases from Stage 1 to Stages 3 + 4; no protein remained significant after FDR correction. Proteins related to endoplasmic reticulum (ER) stress, inflammation and fibrosis became increasingly prominent with advancing CKM stage. Among these, BRD4 increased progressively, whereas circulating klotho declined. CREB3L1 emerged as the strongest clinicoproteomic correlate, robustly associated with both tumor necrosis factor- α (Spearman r = 0.77, FDR < 0.001) and estimated glomerular filtration rate ( r = − 0.72, FDR < 0.001). This study provides the first plasma proteomic atlas across CKM severity and identifies an ER stress-associated molecular signature linked to disease progression. The coordinated changes in CREB3L1, BRD4, and klotho support the hypothesis that ER stress-related pathways contribute to CKM progression and identify candidate biomarkers and therapeutic targets that warrant validation in larger longitudinal cohorts.