Metabolic Signatures in Gastroenteropancreatic Neuroendocrine Neoplasms: Unraveling Diagnostic and Prognostic Insights

Reydson Alcides de Lima-Souza¹Tayna Figueiredo Maciel²Moisés Willian Aparecido Gonçalves²Fernanda Cristina Poscai Ribeiro³Rodrigo A Maioral¹João Figueira Scarini¹Heloisa P Soares⁴Gary Chris Fillmore¹Erika Said Abu Egal^1*

• ¹Biorepository and Molecular Pathology, Huntsman Cancer Institute, Salt Lake City, United States
• ²Universidade Estadual de Campinas, Campinas, Brazil
• ³University of Western (UNOESTE), Guaruja, Sao Paulo, Brazil
• ⁴Department of Oncology, Huntsman Cancer Institute, Salt Lake City, United States

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a heterogeneous group of tumors characterized by diverse biological behaviors and variable clinical outcomes. Recent advances have highlighted the important role of metabolic reprogramming in tumorigenesis, progression, and therapeutic resistance in GEP-NENs. In this review, we synthesize the current evidence on metabolic biomarkers and altered metabolic pathways—particularly those involving glucose, lipid, and amino acid metabolism. Key biomarkers such as GLUT-1, FASN, and enzymes involved in ferroptosis, cholesterol biosynthesis, and amino acid catabolism demonstrate strong associations with tumor aggressiveness, hypoxia, and mTOR signaling. Moreover, metabolomic profiling and functional studies suggest that metabolic markers may inform prognosis and predict response to targeted therapies such as Everolimus. Although promising, the clinical translation of these markers is still limited and requires further validation in large, subtype-specific cohorts. Our findings highlight the importance of integrating metabolic profiling into the diagnostic and therapeutic landscape of GEP-NENs. Future research should prioritize biomarker standardization, multi-omics integration, and the development of metabolism-based therapeutic strategies tailored to tumor subtype and differentiation grade.