Gut Microbiota, Immunity, and Metabolism in the Progression From Chronic Liver Disease to Hepatocellular Carcinoma

The progression from chronic liver injury to hepatocellular carcinoma (HCC) should be viewed as a heterogeneous continuum of immune, metabolic, fibrotic, and microbial remodeling rather than as a single linear route. Although this review uses the MASLD-MASH-fibrosis/cirrhosis-HCC sequence as a mechanistically informative model, the gut-liver-immune framework is also relevant, with important etiology-specific differences, to alcohol-associated liver disease (ALD), chronic hepatitis B virus (HBV) infection, chronic hepatitis C virus (HCV) infection, and mixed-etiology liver disease. Across these contexts, hepatocyte lipotoxicity or viral/alcohol-induced injury, mitochondrial stress, endotoxemia, altered bile-acid signaling, fibrotic remodeling, and immune exhaustion progressively reshape the hepatic microenvironment toward tumor-permissive inflammation and immune escape. We integrate transcriptomic, single-cell, spatial, microbial, and metabolomic evidence to define stage- and etiology-dependent immunometabolic states. Particular emphasis is placed on microbial metabolites, including short-chain fatty acids, secondary bile acids, and tryptophan-derived indoles, which engage host receptors such as FFAR2/3, GPR109A, FXR, TGR5, AhR, and PXR to influence lipid metabolism, epithelial barrier integrity, cytokine programs, epigenetic remodeling, and antitumor surveillance. We further discuss how sex, baseline microbiome composition, hepatic zonation, and preclinical model selection influence disease trajectories and therapeutic responses. By focusing on the gut microbiota-metabolism-immunity axis, this review provides a systems-level framework for biomarker discovery, risk stratification, precision nutrition, and rational combination therapies. Targeting the coordinated interplay among diet, microbiota, metabolism, immunity, and the hepatic spatial niche may help intercept chronic liver disease before malignant transformation and improve therapeutic responses in established HCC.