Genetically instrumented circulating metabolites and hepatobiliary cancer risk: A multi-tiered Mendelian...

Hepatobiliary malignancies-including hepatocellular carcinoma and cholangiocarcinoma-are major causes of cancer-related mortality worldwide, yet their regulatory pathways remain incompletely defined.

We employed a two-sample Mendelian randomization (MR) approach to systematically investigate causal relationships between 1,400 serum metabolites and hepatobiliary cancer risk. Through stringent quality control (all SNPs with F-statistics > 10) and sensitivity analyses (MR-Egger regression, weighted median method, and MR-PRESSO), we identified 10 candidate metabolites.

Meta-analysis confirmed three metabolites with robust associations: risk-increasing dimethylarginine (SDMA+ADMA) and 4-hydroxyhippurate, and protective 3-hydroxyisobutyrate. Multivariable MR validated the independent effects of 4-hydroxyhippurate and 3-hydroxyisobutyrate. In vitro functional experiments demonstrated that 4-hydroxyhippurate promoted, whereas 3-hydroxyisobutyrate inhibited, hepatocellular carcinoma cell proliferation.

These findings advance understanding of metabolic dysregulation in hepatobiliary malignancies and nominate candidate diagnostic biomarkers and therapeutic targets, providing translationally relevant hypotheses for precision medicine.