Frailty is associated with increased coronary artery disease (CAD) risk, but the circulating metabolic features underlying the frailty–CAD relationship and their interplay with genetic susceptibility remain unclear. This study aimed to identify a frailty-related metabolic signature, assess its estimated mediation in the frailty–CAD association, and examine its interaction with genetic risk.

We analyzed 223,907 UK Biobank participants free of CAD at baseline. Frailty was defined using a five-component phenotype model. In 122,959 participants with nuclear magnetic resonance metabolomic data, 169 metabolites were regressed on frailty scores to identify frailty-associated metabolites. Elastic net regression derived a metabolic signature, and Cox proportional hazards models estimated its association with incident CAD. Mediation and interaction analyses assessed mediation by the metabolic signature and interaction with polygenic risk scores.

Over a median 14.8-year follow-up, 17,551 CAD events occurred. Frailty was associated with higher CAD risk (hazard ratio [HR] 1.78; 95% confidence interval [CI] 1.59–1.99). A 36-metabolite frailty-related signature showed an estimated mediation proportion of 18.5% (95% CI 15.7–21.7) in the frailty–CAD association. The association of the metabolic signature with CAD varied across PRS strata on the multiplicative scale, while participants with high PRS and high signature levels had the highest joint CAD risk (HR 3.48; 95% CI 2.95–4.11).

Frailty-related metabolic alterations may partly account for the frailty–CAD association, with associations varying according to genetic susceptibility. Integrating frailty, metabolic, and genetic information may contribute to a more comprehensive understanding of cardiovascular risk.