Cholesterol metabolic rewiring shapes immune remodeling across hepatocarcinogenesis.

Cholesterol metabolism, hepatocellular carcinoma (HCC), and the tumor immune microenvironment are increasingly recognized as interconnected drivers of metabolic dysfunction-associated steatotic liver disease/metabolic dysfunction-associated steatohepatitis-related HCC (MASLD/MASH-HCC). However, cholesterol dysregulation during hepatocarcinogenesis is often discussed as isolated pathways or single-stage events, and evidence strength differs across human HCC tissues, preclinical HCC models, and non-HCC systems. This review integrates mechanistic, spatial multi-omics, and translational evidence to highlight cholesterol dyshomeostasis as a stage- and cell-type-specific rewiring of synthesis, uptake, esterification, efflux, and conversion rather than a uniform metabolic increase. In chronic metabolic liver disease, sterol regulatory element-binding protein 2 (SREBP2)-SREBP cleavage-activating protein (SCAP) activation, impaired bile acid-farnesoid X receptor (FXR) feedback, free-cholesterol loading, and oxysterol accumulation may connect hepatocyte stress with stellate-cell activation, macrophage remodeling, inflammation, and fibrosis. During preneoplastic transition and early HCC, squalene epoxidase (SQLE), sterol O-acyltransferase 1 (SOAT1), farnesyl-diphosphate farnesyltransferase 1 (FDFT1), 24-dehydrocholesterol reductase (DHCR24), and SCAP-regulatory circuits may support membrane remodeling, oncogenic signaling, metabolic autonomy, and impaired immune surveillance, although their evidence levels vary. In advanced and metastatic HCC, spatially resolved studies suggest cholesterol-active tumor regions may be coupled to exhausted T cells, tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), extracellular vesicle signaling, and oxysterol-mediated communication. We further discuss stage-aligned diagnostic and therapeutic opportunities, proposing cholesterol metabolic rewiring as a hypothesis-generating and partially validated framework for HCC initiation, progression, recurrence, and therapeutic resistance.