The Shanghai Men's Health Cohort (SMHS) study of 61,469 Chinese men aged 40–74 years analyzed the associations between seven markers of adiposity (such as BMI, waist circumference) and liver cancer risk in 322 cases and 322 controls. Participants with liver cancer had a higher proportion of seropositive HBsAg (63.7% vs. 6.2%). They identified 27 metabolites associated with adiposity and liver cancer, forming a functional network, with pyroglutamic acid being the most consistent (β per doubling with BMI = 0.17; OR for cancer = 1.56). Pathway analysis showed changes in energy, lipid and amino acid metabolism, especially the biosynthesis of phenylalanine, tyrosine and tryptophan. Parallel mediation confirmed the indirect effects of metabolites for six markers of adiposity, with a proportion of 0.16 for BMI. Mendelian randomization supported causality for 23 associations, the strongest between waist circumference and oxoglutaric acid (βIVW = 0.31). The main limitation is the population mismatch between observational (Chinese men) and MR (European) data. Findings identify amino acid, lipid, and energy metabolites as mediators of the link between adiposity and liver cancer.