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Hepatocellular carcinoma, the third leading cause of cancer-related deaths globally, presents a critical public health burden in China due to its high incidence and mortality. While targeted therapies and immunotherapies have improved survival in advanced HCC, drug resistance remains a major therapeutic challenge. Recent studies suggest that gefitinib, an EGFR inhibitor, overcomes lenvatinib resistance, yet its mechanistic underpinnings are incompletely understood. To investigate gefitinib's metabolic effects in HCC, we conducted untargeted metabolomic profiling using two separate platforms: gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-mass spectrometry (LC-MS) with both hydrophilic interaction liquid chromatography (HILIC) and reversed-phase modes. Raw data were processed by Mass Hunter, normalized with internal standards, and analyzed via SIMCA for pattern recognition. Principal component analysis (PCA) of quality control samples and experimental groups (n = 6 each) confirmed system stability and clear inter-group separation. Orthogonal projections to latent structures discriminant analysis models were validated by 200 permutation tests. Analysis identified 42 metabolites with VIP > 1, of which 25 showed significant alterations (p < 0.05) post-gefitinib treatment. KEGG/RaMP-DB enrichment revealed perturbations in four key pathways: arginine-proline metabolism, nitrogen metabolism, branched-chain amino acid biosynthesis, and taurine metabolism. These results delineate gefitinib-induced metabolic reprogramming in HCC cells, providing a foundation for targeting metabolic vulnerabilities to overcome therapy resistance.