GLS encodes glutaminase, a mitochondrial enzyme that catalyzes the hydrolysis of glutamine to glutamate, playing a central role in cellular glutamine metabolism and energy production 1. The enzyme exhibits high expression in various cancer types, including pancreatic ductal adenocarcinoma and colorectal cancer, where it promotes tumor cell proliferation through glutaminolysis 12. GLS activity is regulated by post-translational modifications, particularly succinylation at K311, which enhances oligomerization and enzymatic activity during oxidative stress 1. The enzyme functions in cellular osmoregulation, as demonstrated in corneal epithelial cells under hyperosmotic stress, where GLS-1 upregulation helps maintain ATP production through glutamate conversion for the tricarboxylic acid cycle 3. Cancer cells can adapt to glutamine deprivation or GLS inhibition through compensatory metabolic pathways, such as the serine synthesis pathway, which can produce α-ketoglutarate when glutamate is depleted 4. RNA-binding protein HuR regulates GLS mRNA alternative splicing and stability, controlling the expression of different glutaminase isoforms (GAC and KGA) associated with cancer progression 5. Genetic variations in GLS, including GCA repeat polymorphisms, may influence disease susceptibility and clinical outcomes 67.