Phase-resolved lipid reprogramming in MASLD/MASH-associated hepatocellular carcinoma: pathogenesis, risk interception, and biomarker-matched therapeutic strategies

Metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) are increasingly important substrates for hepatocellular carcinoma (HCC), but their cancer biology cannot be explained by lipid accumulation alone. This review proposes a phase-resolved framework in which the biological role of lipid metabolism changes across the MASLD/MASH-to-HCC continuum. In early disease, excess substrate supply, de novo lipogenesis (DNL), fatty acid oxidation (FAO) imbalance, defective very-low-density lipoprotein (VLDL) export, organelle stress, and gut-liver dysregulation produce hepatic lipid-buffering failure. During transformation, repeated lipotoxic injury is converted into genomic damage, senescence escape, epigenetic and RNA-level stress memory, fibrotic remodeling, immune dysfunction, and microbiome-derived amplification. In established HCC, malignant cells exploit lipid programs, including lipogenesis, selective FAO, carnitine rerouting, lipid uptake, lipid droplet buffering, hypoxic adaptation, and ferroptosis resistance, to support growth and therapy resistance. This stage dependency explains why the same lipid pathway may be protective, neutral, or oncogenic depending on disease phase and cell compartment. It also creates a risk of phase mismatch, in which improvement of steatohepatitis does not necessarily translate into HCC prevention and a tumor vulnerability may be irrelevant earlier in disease. Lipid-directed translation is therefore best framed around phase-specific endpoints and biomarker enrichment, while recognizing that most lipid directed interventions in MASLD-HCC remain investigational outside approved anti-MASH therapies and standard HCC treatment.