Assi N, et al. - Whether metabolic signatures mediate the link between lifestyle factors and hepatocellular carcinoma (HCC) was determined in a nested case–control study within European Prospective Investigation into Cancer and Nutrition (EPIC), where the “meeting-in-the-middle” (MITM) statistical framework was applied and healthy lifestyle index (HLI) variables were related to targeted serum metabolites. A positive association of body mass index (BMI)-associated metabolic component with glutamic acid, tyrosine, PC aaC38:3, and liver function score and a negative association with lysoPC aC17:0 and aC18:2 was noted. The lifetime alcohol-specific signature had negative loadings on sphingomyelins. Overall, the relevant metabolic signatures mediated the link between lifestyle exposures and HCC risk in a refined MITM framework.