{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T04:29:28Z","timestamp":1788496168218,"version":"build-2803163510"},"reference-count":54,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T00:00:00Z","timestamp":1773705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union\u2014NextGenerationEU","award":["ECS00000036"],"award-info":[{"award-number":["ECS00000036"]}]},{"name":"European Union\u2014NextGenerationEU","award":["ECS 00000024"],"award-info":[{"award-number":["ECS 00000024"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Cholangiocarcinoma (CCA) is a rare malignancy of the biliary tree with increasing global incidence and mortality and limited therapeutic options. Intrahepatic cholangiocarcinoma (iCCA) metabolism exhibits enhanced glycolysis, oxidative phosphorylation, and glutamine utilization. In this study, we investigated the therapeutic potential of targeting glutaminolysis in iCCA, identifying glutamate dehydrogenase (GDH)\u2014which converts glutamate to \u03b1-ketoglutarate\u2014as a key metabolic hub. We evaluated the effects of pomegranate waste extract (PWE), a by-product of industrial pomegranate juice production, on cell viability, proliferation, migration, ATP production, and extracellular acidification in CCLP1 cells, an established iCCA model. Our results are consistent with an altered cellular energy metabolism. We further assessed GDH enzymatic activity, expression, and transcriptional regulation in the presence or absence of PWE and its major components, punicalagin and ellagic acid. GDH expression was downregulated by PWE in a dose-dependent manner through inhibition of NF-\u03baB signaling, revealing a new mechanistic link between NF-\u03baB and GDH. In addition, GDH enzymatic activity was dose-dependently inhibited by PWE, as well as punicalagin and ellagic acid. Notably, punicalagin was identified as a novel competitive inhibitor of GDH. Overall, these findings provide the first evidence that modulation of glutaminolysis through GDH targeting impairs iCCA cell growth and metabolism, supporting GDH as a promising metabolic target. This study highlights pomegranate-derived compounds as potential leads for the development of adjunctive or preventive strategies in intrahepatic cholangiocarcinoma.<\/jats:p>","DOI":"10.3390\/biom16030449","type":"journal-article","created":{"date-parts":[[2026,3,17]],"date-time":"2026-03-17T10:21:41Z","timestamp":1773742901000},"page":"449","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inhibition of Glutamate Dehydrogenase as a Potential Strategy to Modulate Intrahepatic Cholangiocarcinoma Cell Metabolism"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8455-4075","authenticated-orcid":false,"given":"Anna","family":"Santarsiero","sequence":"first","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1049-8987","authenticated-orcid":false,"given":"Ilaria","family":"Pappalardo","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Sciences, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-2580-1414","authenticated-orcid":false,"given":"Alessandro","family":"Santarsiere","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Sciences, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4276-4389","authenticated-orcid":false,"given":"Ernesto","family":"Santoro","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Sciences, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2100-6981","authenticated-orcid":false,"given":"Marisabel","family":"Mecca","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Evidente","sequence":"additional","affiliation":[{"name":"Institute of Biomolecular Chemistry, National Research Council (CNR), 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0588-2092","authenticated-orcid":false,"given":"Pierluigi","family":"Reveglia","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Lecce","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3696-9149","authenticated-orcid":false,"given":"Federica","family":"De Carlo","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Calabrese","sequence":"additional","affiliation":[{"name":"Laboratory of Preclinical and Translational Research, Centro di Riferimento Oncologico della Basilicata (IRCCS-CROB), 85028 Rionero in Vulture, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8509-5218","authenticated-orcid":false,"given":"Vittoria","family":"Infantino","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7265-1625","authenticated-orcid":false,"given":"Stefano","family":"Superchi","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Sciences, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Todisco","sequence":"additional","affiliation":[{"name":"Department of Basic and Applied Sciences, University of Basilicata, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/s41575-020-0310-z","article-title":"Cholangiocarcinoma 2020: The next Horizon in Mechanisms and Management","volume":"17","author":"Banales","year":"2020","journal-title":"Nat. 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