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In addition to genetic alterations, metabolic reprogramming is a hallmark of HNSCC and contributes to tumor progression and treatment failure. The hepatocyte growth factor (HGF)\/c-MET signaling pathway is frequently activated in head and neck squamous cell carcinoma (HNSCC), where it promotes tumor cell proliferation, invasion, and increased glucose metabolism. However, its contribution to the regulation of glutamine metabolism in HNSCC remains largely unexplored. Basal GLS-1 expression was compared between primary human oral keratinocytes (HOK) and HNSCC cell lines with distinct MET status (Detroit 562, FaDu, and SCC-154). Subsequently, HNSCC cell lines were stimulated with HGF, and GLS-1 expression was assessed by quantitative PCR and Western blotting. Functional effects were evaluated using wound-healing assays, enzymatic quantification of extracellular glutamine and glutamate, and Seahorse-based mitochondrial respiration analysis. GLS-1 was silenced using siRNA to determine its functional relevance. In addition, transcriptomic data from the TCGA-HNSC cohort were analyzed to evaluate the clinical association between MET signaling, MAPK\/ERK pathway activity, and GLS1 expression. HGF stimulation selectively induced GLS-1 expression in MET-amplified Detroit 562 cells at both mRNA and protein levels, whereas MET wild-type cells remained largely unaffected. Mechanistically, HGF triggered robust ERK1\/2 activation, and pharmacological inhibition of c-MET or ERK signaling abrogated GLS-1 induction. Functionally, HGF increased glutamine consumption, glutamate production, and mitochondrial respiratory capacity in a GLS-1\u2013dependent manner, while GLS-1 silencing significantly impaired HGF-induced cell migration and mitochondrial respiration. Importantly, analysis of TCGA-HNSC tumors revealed significant correlations between MET expression, MAPK\/ERK pathway activity, and GLS1 expression, supporting the clinical relevance of the identified signaling axis. Together, these findings identify GLS-1 as a downstream effector of HGF\/c-MET\u2013MAPK\/ERK signaling in MET-amplified HNSCC and link oncogenic signaling to glutamine metabolism and mitochondrial function. The observed associations in TCGA patient tumors further support the clinical relevance of this pathway and suggest that targeting glutaminase or ERK signaling may represent a promising therapeutic strategy in c-MET\u2013driven HNSCC.<\/jats:p>\n                  <jats:p>\n                    <jats:bold>Graphic abstract<\/jats:bold>\n                  <\/jats:p>\n                  <jats:p>The schematic summarizes the proposed mechanism: HGF binding to the c-MET receptor activates the MAPK\/ERK signaling pathway, resulting in transcriptional upregulation of GLS-1. Increased GLS-1 expression enhances glutamine metabolism and mitochondrial oxidative phosphorylation, thereby promoting metabolic reprogramming and increased cell motility in MET-amplified HNSCC cells. Pharmacologic inhibition of c-MET or ERK1\/2, as well as GLS-1 silencing, disrupts this signaling axis, attenuating both metabolic activity and HGF-driven migration. Collectively, these findings identify GLS-1 as a critical downstream effector of HGF\/c-MET signaling that links oncogenic signaling to metabolic adaptation and tumor progression in HNSCC. Created in BioRender. Schlegel, N. 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