Metabolic crosstalk between fatty acid oxidation and glycolysis underlies glioblastoma viability
Presenter: Marcela Villaverde, PhD Session: Metabolic Studies in Brain, Pediatric, and Hematologic Cancers Time: 4/20/2026 2:00:00 PM → 4/20/2026 5:00:00 PM
Authors
Lola Martinez Ibarguren 1 , Fiorella Orsini Zanetti 1 , Sofia Paz Osorio Rencoret 1 , Maria Florencia Arbe 1 , Marina Perona 2 , Gabriela Salamone 3 , Gerardo Martin Oresti 4 , Pablo J Sáez 5 , Catalina Lodillinsky 6 , Marcela Solange Villaverde 7 1 Universidad de Buenos Aires, Facultad de Medicina, Instituto de Oncología Ángel H. Roffo, Buenos Aires, Argentina, 2 Comisión Nacional de Energía Atómica, Buenos Aires, Argentina, 3 Academia Nacional de Medicina, Instituto de Medicina Experimental, CONICET, Buenos Aires, Argentina, 4 Instituto de Investigaciones Bioquimicas de Bahia Blanca (INIBIBB, CONICET-UNS), Bahia Blanca, Argentina, 5 Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg, Germany, 6 Universidad de Buenos Aires, Facultad de Medicina, Instituto de Oncología Ángel H Roffo, Buenos Aires, Argentina, 7 Universidad de Buenos Aires, Facultad de Medicina, Instituto de Oncología Ángel H. Roffo, CONICET, Buenos Aires, Argentina
Abstract
Metabolic rewiring supports glioblastoma (GB) progression, yet the contribution of fatty acid oxidation (FAO) to GB metabolic plasticity remains poorly defined. GB tumors display elevated expression of FAO-related genes, including carnitine palmitoyltransferase 1A (CPT1A), suggesting a potential reliance on this pathway. Here, we evaluated the functional relevance of FAO in U251 GB cells using etomoxir (ETO), a CPT1A inhibitor. ETO markedly reduced cell viability in monolayers (5-day exposure) and 3D spheroids (9-day exposure; IC50=118 µM) and rapidly disrupted spheroid architecture within 48 hours. Short-term treatment with 200 µM ETO did not alter cell size or granularity, but FAO inhibition induced a clear metabolic shift characterized by increased glucose consumption, elevated lactate release, and enhanced extracellular acidification, consistent with compensatory glycolytic upregulation. To test whether this adaptive response creates a metabolic vulnerability, we inhibited glycolysis with 2-deoxyglucose (2DG). Combined ETO+2DG treatment significantly potentiated cytotoxicity compared with either agent alone after 72 hours. These findings indicate that FAO serves as a relevant energy source in GB cells and that its inhibition triggers increased glycolytic flux as a compensatory mechanism. Together, our data reveal a targetable FAO-glycolysis crosstalk in GB and support the therapeutic potential of dual metabolic pathway inhibition to exploit GB metabolic flexibility.
Disclosure
L. Martinez Ibarguren, None.. F. Orsini Zanetti, None.. S. Osorio Rencoret, None.. M. Arbe, None.. M. Perona, None.. G. Salamone, None.. G. M. Oresti, None.. P. Sáez, None.. C. Lodillinsky, None.. M. S. Villaverde, None.
Cited in
Control: 8485 · Presentation Id: 9204 · Meeting 21436