Regulatory Role and Biomarker Potential of Gut Microbiota Metabolites in the Progression of Metabolic dysfunction-associated steatotic liver disease (MASLD) to Hepatocellular Carcinoma (HCC).

Nonalcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease worldwide. It is now updated as metabolic dysfunction-associated steatotic liver disease (MASLD). The progression of MASLD to hepatocellular carcinoma (HCC) involves complex mechanisms, with the gut microbiota and its metabolites playing a pivotal role in this transformation through the "gut-liver axis." This review systematically summarizes the characteristics of gut microbiota dysbiosis in NAFLD patients and the regulatory mechanisms of its metabolites (e.g., short-chain fatty acids [SCFAs], secondary bile acids, trimethylamine N-oxide [TMAO], and lipopolysaccharides [LPS]) in the progression from MASLD to HCC. SCFAs exert protective effects in the early stages by enhancing the intestinal barrier and modulating immune and metabolic responses. However, metabolic disturbances, such as the "paradoxical effect" of butyrate and the lipogenic effect of acetate, may promote the formation of a tumor microenvironment in the later stages. Secondary bile acids (e.g., deoxycholic acid) exacerbate liver fibrosis and carcinogenesis by activating inflammatory pathways (NF-κB, MAPK), inducing oxidative stress, and inhibiting foresaid X receptor (FXR) signaling. TMAO directly drives HCC progression by activating the MAPK/NF-κB pathway, promoting epithelial-mesenchymal transition (EMT), and creating an immunosuppressive microenvironment. LPS accelerates fibrosis and metabolic reprogramming through TLR4-mediated chronic inflammation and hepatic stellate cell activation. This review highlights that the dynamic changes in gut microbiota metabolites are closely associated with MASLD -HCC progression. Specific monitoring of these metabolites may serve as potential biomarkers for early detection. Furthermore, gut-targeted therapies (e.g., fecal microbiota transplantation) have shown translational potential. Future studies are needed to further validate their clinical value and develop precise prevention and treatment strategies.