Exploring the association between gut microbiota metabolites and hepatocellular carcinoma via network pharmacology.

[BACKGROUND] Gut microbiota plays a pivotal role in human homeostasis and health. This study adopted network pharmacology to clarify the metabolic transformation of gut microbiota metabolites and their molecular mechanisms in hepatocellular carcinoma (HCC) pathogenesis, aiming to unravel the complex crosstalk between gut microbiota, metabolites, and key genes.

[METHODS] Gut microbiota metabolites and their associated genes were retrieved from the gutMGene database. Metabolite target genes were predicted using the SEA and STP databases, while HCC-related genes were compiled from GeneCards, OMIM, and CTD. Intersection analysis identified key genes mediating metabolite-regulated HCC progression. Core genes were screened via a protein-protein interaction (PPI) network, and comprehensive Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were further performed. A "microbiota-substrate-metabolite-target" network was constructed, and metabolites were evaluated for drug-likeness and toxicity to identify therapeutic candidates.

[RESULTS] A total of 52 key genes involved in the gut microbiota-HCC interaction were screened, with , , and as hub genes. The Microbial Substrate Metabolite Target (M-S-M-T) network showed these hubs regulate HCC via 8 metabolites, 5 substrates, and 20 microorganisms. GO enrichment analysis indicated these key genes were mainly enriched in bacterial molecule response, membrane rafts, and DNA-binding transcription factor binding. KEGG enrichment analysis showed they were primarily associated with PI3K-Akt, MAPK, and Toll-like receptor signaling pathways. Three metabolites exhibited HCC therapeutic potential.

[CONCLUSIONS] Gut microbiota metabolites may exert regulatory effects on HCC mainly by targeting core genes. Targeting these genes in the regulatory network may offer a novel multidimensional therapeutic approach for HCC, and the identified metabolites could act as potential therapeutic candidates for HCC.