Reframing cholangiocarcinoma through lipid metabolism: a three-phase conceptual review

Cholangiocarcinoma (CCA) remains a highly lethal and biologically heterogeneous malignancy for which effective early detection and durable systemic therapies are still lacking. Accumulating evidence suggests that lipid metabolic reprogramming is not merely a bystander phenomenon in CCA but a functionally relevant process linked to tumor initiation, progression, immune evasion, metastasis, and therapeutic resistance. However, the current findings remain fragmented across disease subtypes, experimental systems, and analytical platforms. In this review, we synthesize studies published over the past decade and propose a conceptual three-phase framework—initiation, amplification, and adaptation—to organize current evidence on lipid metabolism in CCA. In the initiation phase, inflammatory lipid mediators, cholestatic lipids, and etiology-specific metabolic disturbances may create a permissive environment for malignant transformation. In the amplification phase, enhanced fatty acid uptake, de novo lipogenesis, cholesterol remodeling, and lipid–immune crosstalk increase tumor growth and immunosuppression. In the adaptation phase, fatty acid oxidation, metastatic colonization programs, and ferroptosis resistance support dissemination and treatment failure. We further discuss how lipid-associated signatures in serum, bile, exosomes, and tissues may complement conventional biomarkers in specific diagnostic settings, and we evaluate therapeutic strategies targeting lipid uptake, synthesis, oxidation, cholesterol homeostasis, and lipid-mediated immune remodeling. Importantly, we highlight major limitations in the current evidence, including marked intertumoral heterogeneity, reliance on preclinical models, and the lack of standardized lipidomics workflows. Rather than defining a validated biological staging system, this framework is intended as a heuristic model to guide mechanistic investigation, biomarker development, and metabolism-informed therapeutic stratification in CCA.