The Roles and Clinical Significance of Major Hepatic-Derived Metabolites in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is increasingly recognized as a metabolically orchestrated malignancy, in which hepatic-derived metabolites function not only as byproducts of liver physiology but also as active modulators of tumor biology. This review systematically explores the multifaceted roles of five major classes of hepatic-derived metabolites-bile acids (BAs), albumin, coagulation factors, alpha-fetoprotein (AFP), and fat-soluble vitamins (A, D, and K)-in HCC initiation, progression, prognosis, and therapeutic responsiveness. We highlight emerging evidence that dysregulation of BAs and their bidirectional crosstalk with gut microbiota contributes to inflammation, immune evasion, and tumor heterogeneity. Albumin, beyond its function as a liver function marker, exhibits tumor-suppressive properties through modulation of cell cycle and invasion-related pathways. Coagulation factors such as FVII, FIX, and FXa influence autophagy, metastasis, and tumor immunity. AFP, traditionally used as a diagnostic marker, has shown functional roles in oncogenic signaling and immunosuppression. Meanwhile, fat-soluble vitamins interact with nuclear receptors (e.g., VDR, RXR, and PXR) to regulate gene transcription, BA metabolism, and the tumor microenvironment. We further discuss the prognostic utility of integrated metabolite-based models such as ALBI, BALAD, and GALAD scores and emphasize the potential of combining metabolic signatures to enhance risk stratification and guide personalized therapy. In conclusion, hepatic-derived metabolites represent a mechanistic bridge between liver physiology and HCC pathogenesis, offering novel opportunities for biomarker discovery and therapeutic innovation.