Mechanisms and therapeutic implications of interactions between the gut microbiome and host epigenetics in hepatocellular carcinoma

This narrative review summarizes current evidence on reciprocal interactions between the gut microbiome and host epigenetic regulation in hepatocellular carcinoma (HCC), with emphasis on mechanistic pathways and potential translational implications. Disruption of the intestinal barrier can increase hepatic exposure to microbial products and activate inflammatory signaling, including toll-like receptor 4 (TLR4)-nuclear factor kappa B (NF-κB) and interleukin 6 (IL-6)-Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) pathways, which may interact with epigenetic regulators. Microbiota-derived short-chain fatty acids can modulate histone deacetylase (HDAC) activity and acetylation-related processes, while microbiota-dependent bile acid remodeling influences hepatic metabolic and immune signaling through receptors such as farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Polyamine, one-carbon, and α-ketoglutarate-related metabolism provide plausible biochemical links between microbial metabolism and DNA or RNA modification, although direct causal evidence for these connections in HCC remains limited. HCC-specific studies also support roles for N6-methyladenosine (m6A) regulation in metabolic reprogramming and antitumor immunity, whereas evidence that host epigenetic regulation reshapes the gut microbiota derives mainly from non-HCC intestinal models. These findings highlight a heterogeneous evidence base in which selected microbiome-metabolite-host pathways are mechanistically supported, while others remain inferential. Future studies should integrate longitudinal microbiome and metabolite profiling with cell-resolved epigenomic, immune, and clinical data. These approaches may help identify reproducible biomarkers and mechanistically validated therapeutic targets. However, prospective and experimental validation remains necessary before microbiome- or epigenetics-based strategies can inform routine HCC management.