Association between metabolites and hepatocellular carcinoma: findings from a two-sample Mendelian randomization study.

[BACKGROUNDS/AIMS] Identifying metabolic biomarkers can enhance early detection and risk stratification of hepatocellular carcinoma (HCC). We conducted a two-sample Mendelian randomization (MR) study to assess the potential causal effects of metabolites on HCC risk.

[METHODS] We performed meta-analyses to pool the effects of genetic instruments from 64 previously published genome-wide association studies. Summary statistics for HCC were obtained from a meta-analysis of the UK BioBank and FinnGen cohorts. MR analyses for the association between 3,275 metabolites and HCC risk were performed using inverse variance weighted, weighted median, MR-Egger, and MR-PRESSO methods to estimate the association. Enrichment analyses were performed on the significant metabolites to identify biological pathways associated with macronutrient intake.

[RESULTS] We identified 99 metabolites that were positively and 36 metabolites that were negatively associated with HCC risk. Methyl glucopyranoside and phosphatidylcholine C38:3 were positively associated with HCC risk, whereas while 3-dehydrocarnitine and 10-undecenoate were inversely associated, with no evidence of heterogeneity, pleiotropy, or outlier effects for any of these associations. Pathway enrichment analysis showed that metabolites associated with increased HCC risk were primarily related to amino acid transport and solute carrier transporter disorders, whereas those linked to reduced risk were mainly involved in inositol and phosphatidylinositol metabolism, glycerophospholipid catabolism, and MeCP2-related regulatory processes.

[CONCLUSIONS] This comprehensive MR study identified several metabolites with potential causal roles in HCC development. Our findings highlight nutrient transport, lipid metabolism, and related regulatory mechanisms as key components of HCC pathogenesis, offering new avenues for biomarker discovery and therapeutic intervention.