PFKFB2 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2) is a bifunctional enzyme that catalyzes synthesis and degradation of fructose-2,6-bisphosphate (F-2,6-BP), a critical allosteric activator of phosphofructokinase-1 and key regulator of glycolysis 1. The 505-amino acid heart isoform protein retains important regulatory and catalytic sites conserved across mammalian species 1. PFKFB2 function extends beyond basic glycolytic regulation to encompass immune cell metabolism and disease pathogenesis. HIF-1α directly transactivates PFKFB2 to promote glycolysis-driven dendritic cell maturation and exacerbate acute lung injury 2. Similarly, Pim2 kinase phosphorylates PFKFB2 at serine 466 to enhance M1 macrophage polarization in inflammatory arthritis 3. In cancer metabolism, PFKFB2 supports glioblastoma growth by fueling glucose-derived serine biosynthesis under nutrient stress 4. PFKFB2 dysregulation associates with multiple disease states: chr1 kidney disease 5, heart failure pathogenesis 6, and ERBB2-driven breast cancer susceptibility 7. The complex, context-dependent roles of PFKFB2 in metabolic reprogramming across immune and cancer cells highlight its emerging therapeutic potential 8.