Multi-omics profiling reveals CKM syndrome severity as a gradient risk factor for cancer: A prospective cohort study

Objective
Cardiovascular-Kidney-Metabolic (CKM) syndrome, a multisystem disorder, has been linked to cardiovascular and metabolic morbidity, but its association with cancer risk remains poorly characterized. This study aimed to examine the relationship between CKM syndrome severity and the incidence of overall cancer and 18 site-specific cancers, and to identify potential mediating plasma protein and metabolite signatures.
Methods
We analyzed data from 351,239 participants in the UK Biobank, classified into five CKM syndrome stages (0–4). Plasma proteomic (2923 proteins) and metabolomic (168 metabolites) profiles were analyzed. Cox models evaluated associations, and mediation analyses identified biological mediators.
Results
Over a median 13.5-year follow-up, 44,840 incident cancer cases were documented. Advancing CKM stages (0–3) showed a dose-response relationship with increased overall (per one-stage increase: adjusted HR, 1.05; 95%CI, 1.03–1.07) and eleven site-specific cancer risks (e.g., digestive, respiratory, urinary tracts) (per one-stage increase: adjusted HR ranging from 1.06 to 1.46). Stage 4 remained associated with elevated risk, though attenuated versus stage 3. Multi-omics mediation analysis identified 22 proteins and 2 metabolites that partially mediated the association between CKM stages 0–3 and overall cancer risk, implicating immune and metabolic pathways. Functional enrichment analysis further highlighted the PI3K-Akt signaling pathway and inflammatory processes as key mechanistic contributors.
Conclusions
CKM syndrome severity is independently associated with increased cancer risk, partially mediated by proteins and metabolites involved in inflammation, proliferation, and lipid metabolism. These findings support CKM staging as a multisystem disorder with significant oncological implications and highlight potential biomarkers for intervention.