Abstract
The underlying metabolic mechanisms between healthy lifestyle behaviors and a lower risk of chronic liver diseases (CLD) remain elusive. This prospective cohort study of 168,260 UK Biobank participants without baseline liver disease identified a healthy lifestyle-associated metabolic signature using elastic net regression and examined its relationship with CLD. The resulting signature, comprising 66 metabolites, was strongly correlated with healthy lifestyle scores (r = 0.434, P < 0.001) and was inversely associated with the risks of MASLD, cirrhosis, liver cancer, and liver-related mortality, with hazard ratios ranging from 0.55 to 0.70 per standard deviation increase. Mediation analyses showed that this metabolic signature explained 20.3-49.6% of the protective effects of a healthy lifestyle on these CLDs, while Mendelian randomization suggested potential causal roles of these metabolites in CLD development. Overall, the findings underscore the importance of early lifestyle interventions and metabolic monitoring for the precise prevention of CLD.