GFPT2 (glutamine-fructose-6-phosphate transaminase 2) is the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), catalyzing conversion of fructose-6-phosphate and glutamine to glucosamine-6-phosphate and thereby controlling glucose flux into this pathway 1. Via HBP regulation, GFPT2 likely controls precursor availability for N- and O-linked protein glycosylation 1. Unlike its paralog GFPT1, GFPT2 exhibits substantially reduced feedback inhibition by UDP-N-acetylglucosamine, enabling sustained pathway activation when paired with AMDHD2 1. GFPT2 has emerged as a critical metabolic vulnerability in multiple malignancies. In KRAS/LKB1 co-mutant lung cancer, GFPT2 inhibition selectively reduces tumor growth in vitro and in vivo 2. In pancreatic cancer, GFPT2-mediated O-GlcNAcylation of YBX1 promotes IL-18 transcription, facilitating M2 macrophage polarization and immunosuppression 3. GFPT2 overexpression in tumor cells impairs macrophage mitochondrial fission needed for antibody-mediated phagocytosis, representing a targetable immune evasion mechanism 4. In mesothelioma, GFPT2 activates NF-κB signaling through p65 O-GlcNAcylation, promoting malignant progression with 92.6% diagnostic sensitivity 5. Genetically, GFPT2 polymorphisms associate with type 2 diabetes and diabetic nephropathy, with certain variants increasing mRNA levels and hexosamine flux 6.