Across 355,724 UK Biobank participants followed for a median 13.5 years, a multi-omic analysis mapped cardiovascular-kidney-metabolic (CKM) syndrome stages 0–3 onto incident cardiovascular disease using proteomics (n=37,785) and metabolomics (n=190,112). LASSO and XGBoost-SHAP models identified a stage-ordered molecular continuum: ADM mediated 42.9% of CVD risk in Stage 1 (metabolic/extracellular matrix dysregulation), FABP4 accounted for 24.6% in Stage 2 (inflammation), and HAVCR1 explained 28.0% in Stage 3 (hypoxia/fibrosis). High cardiovascular health scores (Life's Crucial 9 ≥80) were associated with ~80% lower CVD risk in Stages 0–2, partly mediated through these same molecules.
This preprint — not yet peer-reviewed — represents one of the largest multi-omic dissections of CKM syndrome to date and offers a mechanistic vocabulary that the field has lacked since CKM staging was formalized by the AHA in 2023. The sequential shift from ECM remodeling to systemic inflammation to organ fibrosis mirrors what clinicians observe clinically but now has molecular anchors that could, in principle, guide stage-adapted biomarker panels or therapeutic targets. HAVCR1 (KIM-1) as the dominant Stage 3 mediator aligns with established kidney injury biology, lending biological plausibility. Key limitations include the observational design, the predominantly European UK Biobank cohort limiting generalizability, and mediation estimates that are statistical rather than causal. Whether targeting ADM or FABP4 pharmacologically would recapitulate the lifestyle-driven CVH benefit remains entirely untested. Paradigm-shifting in framework; confirmatory validation in diverse cohorts is essential.