GLS2 (glutaminase 2) catalyzes the conversion of glutamine to glutamate and α-ketoglutarate, playing a central role in glutaminolysis and mitochondrial energy metabolism 1. Beyond canonical metabolic functions, GLS2 exhibits context-dependent roles in cancer biology. In hepatocellular carcinoma (HCC), GLS2 functions as a bona fide tumor suppressor 1. Mechanistically, GLS2 promotes ferroptosis—an iron-dependent form of cell death—by facilitating α-ketoglutarate production and subsequently increasing lipid reactive oxygen species 1. Gls2 knockout mice develop larger HCC tumors and spontaneous lymphomas, while ectopic GLS2 expression reduces xenograft tumor size in a ferroptosis-dependent manner 1. GLS2 also exhibits non-canonical functions: in pancreatic ductal adenocarcinoma, GLS2 undergoes K151 acetylation under hypoxia, enabling YAP1 interaction and promoting PD-L1 upregulation, thereby facilitating immune evasion 2. Additionally, GLS2 participates in metabolic-epigenetic regulation; METTL14-mediated m6A modifications control GLS2 translation efficiency, affecting hepatic oxidative stress and immune cell recruitment during fatty liver disease progression 3. However, GLS2's role demonstrates significant context-dependency: expression patterns and tumor-suppressive versus tumor-promoting functions vary across cancer types 4. These findings suggest GLS2 represents a therapeutic target with cancer-type-specific implications.