Lipidome as a ferroptotic rheostat in cholangiocarcinoma: A proposed model and its current evidence base.

Cholangiocarcinoma (CCA) is a biliary epithelial malignancy of relentless lethality, whose therapeutic intractability is inseparable from its radical metabolic reprogramming. Ferroptosis, an iron-catalysed, lipid-hydroperoxide-mediated form of regulated cell death, has emerged as a compelling therapeutic vulnerability in CCA. However, exploiting this vulnerability demands a mechanistic account of how CCA cells engineer their membrane lipidome to escape ferroptotic execution. This review advances the argument that the ratio of monounsaturated fatty acid (MUFA)-containing phosphatidylethanolamines (PEs) to polyunsaturated fatty acid (PUFA)-PEs within the plasma membrane may constitute a principal determinant of ferroptotic fate in CCA, a proposed dynamic equilibrium we term the "ferroptotic rheostat." We synthesise the available lipidomic, metabolomic, and functionally integrated evidence across multiple CCA datasets, centering on the acyl-CoA synthetase long-chain family member 3 (ACSL3)-driven MUFA enrichment of CCA cell membranes as the most direct, although still single-study, CCA-specific evidence for a membrane-lipid-based ferroptosis resistance mechanism. We state at the outset that the rheostat is advanced as a working hypothesis and a proposed model, not as an established mechanism. It rests on a single untargeted lipidomic study in four CCA cell lines, and the membrane MUFA-PE: PUFA-PE ratio has not been measured directly in human CCA tumour tissue by any published study. We further contextualise how de novo lipogenesis through the fatty acid synthase (FASN)-stearoyl-CoA desaturase-1 (SCD1) axis, ATP-citrate lyase (ACLY)-dependent acetyl-CoA supply, and CCA-specific bile acid-farnesoid X receptor (FXR)-lipid metabolism crosstalk collectively tune rheostat position. We emphasise, however, that apart from the ACSL3-MUFA axis the individual links of this framework are at present supported largely by transcriptomic, bioinformatic, or cross-tumour evidence rather than by direct redox lipidomic measurement in human CCA tissue, and we therefore flag these steps explicitly as hypotheses throughout. The oncometabolic consequences of isocitrate dehydrogenase (IDH1/2) mutations, mediated through 2-hydroxyglutarate (2-HG) and NADPH depletion, are discussed as a genetically defined entry point for ferroptosis sensitisation in a 15-20% iCCA subset. We conclude by outlining priority research gaps, including the systematic application of redox phospholipidomics and spatial lipidomics to human CCA biospecimens, and set out the measurements that would be required to test, refute, or refine the proposed model before a lipid-centric intervention strategy could be considered in CCA.