Beyond fibrosis: the molecular roadmap from MASLD to hepatocellular carcinoma

Metabolic dysfunction-associated steatotic liver disease (MASLD) has overtaken viral hepatitis as the fastest-growing cause of hepatocellular carcinoma (HCC) in most high-income countries. What makes this epidemic clinically treacherous is a feature that distinguishes MASLD-related HCC from other aetiologies: roughly half of all cases arise in livers that have never progressed to cirrhosis, slipping through the net of conventional surveillance strategies. The molecular journey from fatty liver to malignancy unfolds through at least six interlocking programmes: lipotoxic rewiring of hepatocyte metabolism, including acquired lysosomal acid lipase (LAL) dysfunction, oncogenic glucose reprogramming through the p53-PUMA-mitochondrial pyruvate carrier (MPC) axis, and a preliminary MLKL–Mfn2 axis linking metabolic stress to mitochondrial dysfunction; a chronic shift in the hepatic immune milieu toward tumour-permissive tolerance; gut microbiota dysbiosis flooding portal circulation with pro-inflammatory metabolites; progressive collapse of autophagic flux with p62/SQSTM1 accumulation and lipolysosome formation; and pervasive epigenetic rewriting spanning DNA methylation, novel histone marks, and non-coding RNA networks. We also discuss emerging biomarkers and therapeutic strategies, closing with a brief note on Doublecortin-like kinase 1 (DCLK1) as a candidate marker at the intersection of cancer stem cell identity and immune microenvironment subversion.