The causal association between plasma proteomes and the risk of developing hepatocellular carcinoma (HCC) in human populations has not been fully elucidated. Mendelian randomization (MR) is an innovative epidemiological study design that enables the unbiased identification of causal relationships by utilizing genetic variants as instrumental variables. Consequently, we employed a two-sample MR approach to investigate the potential causal link between plasma protein levels and the incidence of HCC. A comprehensive bidirectional two-sample MR analysis was performed using genome-wide significant published genome-wide association studies of plasma proteomes (N: 35,559 healthy individuals) and HCC (168 cases and 372,016 controls). Sensitivity analyses were conducted for identified causal proteins. Furthermore, we pursued pathway exploration using Kyoto Encyclopedia of Genes and Genomes and gene ontology analyses. Protein–protein interaction network analysis provided insights into plasma protein–HCC interactions. We identified 17 plasma proteins causally associated with HCC risk ( P IVW < .05). Sixteen proteins were positively associated, including TMCC3, METTL1, SNRPF, KRT19, MED4, RFNG, IL26, NRXN1, MSH2, CLCA2, AKT2, CRYZL1, RDH16, CSF3, CPA4 and COPS7B, while EPHA2 was inversely associated. Gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses implicated key gene correlations with JAK-STAT, PI3K-AKT and chemokine pathways. The protein–protein interaction network highlighted potential plasma protein–HCC relationships. Our genetics-based approach provides evidence supporting a causal role for specific plasma proteomes in influencing HCC risk. Results support causal effects on HCC for TMCC3, METTL1, SNRPF, KRT19, MED4, RFNG, IL26, NRXN1, MSH2, CLCA2, AKT2, CRYZL1, RDH16, CSF3, CPA4, EPHA2, and COPS7B. Experimental validation and mechanistic study are warranted to confirm findings.
Chen et al. (2026) studied this question.