Exogenous chemical exposures are a global health concern due to their hepatotoxic potential, yet the extent to which endogenous metabolic disruption bridges these exposures to long-term liver cancer risk remains unclear. In a nested case-control study within a prospective Chinese cohort (n = 200), we conducted a metabolome-wide association analysis integrating 254 serum exogenous chemical residues with 478 endogenous metabolites to characterize pre-diagnostic metabolic disorders occurring up to 10 years before liver cancer onset and to delineate exposure-risk relationships. Individuals who later developed liver cancer exhibited pronounced metabolic perturbations, particularly involving bile acid metabolism, acylcarnitine pathways, glycerophospholipid turnover, sphingomyelin composition, and acylglycerol metabolism. A candidate early-warning panel comprising Phe/Tyr, FFA 24: 1, PC (16: 0₂0: 5), TG (18: 1₁8: 1₂1: 0), and TG (18: 3₁7: 1₁8: 2) was identified for liver cancer risk stratification. Exposure to salmeterol, diethylstilbestrol, and dibutyl phosphate showed positive associations with liver cancer risk, and mediation analysis highlighted tyrosine, PC (19: 0₁8: 2), and SM (d18: 1/24: 1) as significant intermediators, suggesting hepatocarcinogenesis arises from the combined impact of exogenous chemical exposure and endogenous metabolic disorders. Overall, these findings indicate that early disturbances in bile acid, lipid, and amino acid metabolism precede clinical diagnosis by years and may serve as mechanistic links and early-warning biomarkers for exposure-related liver carcinogenesis.
Fang et al. (Wed,) studied this question.