A blood-based lipid biomarker approach identified sphingomyelin (30:1; O2) as a serum signal that outperformed conventional tumor markers in distinguishing intrahepatic cholangiocarcinoma from hepatocellular carcinoma. The study positions lipidomic profiling as a potentially higher-specificity alternative in clinically adjacent liver cancers where misclassification can delay correct therapy selection. If validated in larger independent cohorts, a single-lipid classifier could simplify diagnostic pathways compared with broader multi-marker panels, improving speed and reducing uncertainty at diagnosis.