{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T20:45:07Z","timestamp":1784234707117,"version":"3.55.0"},"reference-count":80,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"European Union-Next Generation EU through the Italian Ministry of University","award":["CUP D73C22001230006"],"award-info":[{"award-number":["CUP D73C22001230006"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Head and neck squamous cell carcinoma (HNSCC) is the most common and aggressive histologic subtype of head and neck cancer (HNC), difficult to treat effectively. Here, we discuss several studies on human and mouse HNSCC cell lines arising from the mucosal epithelium of various anatomical sites, as well as recent studies using murine models, focused on targeting key checkpoints in the glutamine (Gln) metabolism pathway, either alone or in synergy with other signaling pathways, as a potential therapeutic strategy for HNSCC. Emerging evidence demonstrates a complex interplay between Gln metabolism and pathways mediating altered cellular mechanisms, including ferroptosis, immune system evasion, mitochondrial energy production, and oncogenic transcriptional control. This review examines currently available gene expression databases and protein expression analyses of Gln metabolism-related components in tissue samples from HNSCC patients. From a translational perspective, the co-administration of pharmaceutical agents and biologic products targeting distinct molecular pathways, integrated with radiotherapy (RT) or chemotherapy (CT), may produce superior anti-HNSCC efficacy, thereby improving clinical outcomes and extending patient survival. Multimodal strategies represent a key direction in precision oncology, enabling personalized therapeutic interventions to suppress metastatic dissemination and disease progression more effectively. Therefore, an integrated therapeutic approach represents a promising path to defeat HNSCC.<\/jats:p>","DOI":"10.3390\/cells14241962","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T12:20:57Z","timestamp":1765369257000},"page":"1962","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Interplay Between Glutamine Metabolism and Other Cellular Pathways: A Promising Hub in the Treatment of HNSCC"],"prefix":"10.3390","volume":"14","author":[{"given":"Teresa Stefania","family":"Dell\u2019Endice","sequence":"first","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8099-3505","authenticated-orcid":false,"given":"Francesca","family":"Posa","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppina","family":"Storlino","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenzo","family":"Sanesi","sequence":"additional","affiliation":[{"name":"Department of Medicine and Surgery, Kore University of Enna, 94100 Enna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6127-6105","authenticated-orcid":false,"given":"Lucio","family":"Lo Russo","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6731-0247","authenticated-orcid":false,"given":"Giorgio","family":"Mori","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Foggia, Viale Pinto 1, 71122 Foggia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Barsouk, A., Aluru, J.S., Rawla, P., Saginala, K., and Barsouk, A. 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