PFKFB4 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4) is a bifunctional metabolic enzyme that synthesizes and degrades fructose-2,6-bisphosphate, a potent allosteric activator of phosphofructokinase-1 and key regulator of glycolysis 1. Beyond its canonical metabolic role, PFKFB4 functions as a signaling hub that couples glucose metabolism to transcriptional reprogramming by phosphorylating the coactivator SRC-3 at serine 857, enhancing SRC-3-mediated transcriptional activity and promoting glucose flux toward anabolic pathways 23. PFKFB4 expression is upregulated across multiple cancer types including breast, cervical, endometrial, lung squamous cell carcinoma, pancreatic, and glioma, where it drives enhanced glycolysis and supports aggressive tumor phenotypes 24356. In glioma stem cells, PFKFB4 mRNA stabilization by lactylated PTBP1 sustains glycolytic reprogramming and stemness maintenance 6. PFKFB4 activity is regulated by phosphorylation; PIM2-mediated phosphorylation at threonine 140 promotes its function in endometriosis 7, while THOC3-YBX1 complexes control PFKFB4 mRNA export and stability 8. Clinical evidence demonstrates PFKFB4 elevation correlates with poor prognosis, metastasis, and advanced pathological stage across malignancies 243, positioning PFKFB4 as a promising therapeutic target for cancer treatment 5.