From dysbiosis to malignancy: decoding gut-driven pathways to clinical management in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is undergoing a profound global epidemiological shift, transitioning from viral-driven etiologies to metabolic dysfunction-associated steatotic liver disease (MASLD). This transition challenges traditional cirrhosis-centric surveillance, as a significant proportion of MASLD-HCC develops in non-cirrhotic livers. Parallel to these metabolic shifts, the gut-liver axis has emerged as a central orchestrator of hepatocarcinogenesis. This review decodes the complex gut-driven pathways fueling HCC, highlighting the oncogenic consequences of structural and functional dysbiosis. Dietary patterns and etiology-specific microbial shifts compromise the intestinal and gut-vascular barriers, precipitating a structural "leaky gut". This disruption facilitates the robust translocation of pathogen-associated molecular patterns (PAMPs), particularly lipopolysaccharide (LPS), and toxic microbial metabolites like secondary bile acids, specifically deoxycholic acid, into the portal circulation. Consequently, hepatic innate immunity is chronically activated via Toll-like receptor 4 (TLR4) signaling on Kupffer and hepatic stellate cells, fostering metainflammation, cellular senescence, genomic instability, and a highly immunosuppressive, pro-tumorigenic microenvironment. Furthermore, the depletion of keystone commensals diminishes the protective reservoir of short-chain fatty acids (SCFAs), exacerbating oncogene activation. Translating these mechanistic insights into the clinic, we explore the utility of distinct microbial signatures and metabolomic profiles as non-invasive diagnostic biomarkers. Such tools are urgently needed to bridge the early-detection gap in the expanding MASLD demographic. Finally, we discuss the pivotal role of the microbiome in modulating responses to immune checkpoint inhibitors (ICIs), notably through immune-stimulating taxa like Akkermansia muciniphila, and outline emerging gut-targeted therapies, including next-generation probiotics and fecal microbiota transplantation, aimed at restoring host-microbiome homeostasis to prevent and manage HCC. By decoding these gut-driven pathways, this review provides a comprehensive framework for integrating the microbiome-onco axis into precision oncology, offering novel avenues to combat the rising global burden of hepatocellular carcinoma.