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Simple Summary: Metabolic flexibility is one of the key hallmarks of cancer and metabolites are the final products of this adaptation, reflecting the aberrant changes of tumors. However, the metabolic plasticity of each cancer type is still unknown, and specifically to date, there are no data on metabolic profile in neuroendocrine tumors. The aim of our retrospective study was to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. We provided, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use, selecting a reduced set of metabolites of high diagnostic accuracy. We have identified 32 novel enriched metabolic pathways in NETs related with the TCA cycle, and with arginine, pyruvate or glutathione metabolism, which have distinct implications in oncogenesis and may open innovative avenues of clinical research. Purpose: High-throughput "-omic" technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. Methods: Plasma samples from 77 NETs and 68 controls were profiled by GC−MS, CE−MS and LC−MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential. Results: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential. Conclusions: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research. [ABSTRACT FROM AUTHOR]