PFKFB4 encodes a bifunctional enzyme that synthesizes and degrades fructose-2,6-bisphosphate, a potent allosteric activator of glycolysis. Beyond its canonical metabolic role, PFKFB4 functions as a metabolic-transcriptional hub: it phosphorylates the coactivator SRC-3 at serine 857, enhancing transcriptional programs that drive glucose flux toward biosynthetic pathways including the pentose phosphate pathway and purine synthesis 1. In glioma stem cells, PFKFB4 mRNA stability is enhanced by lactylated PTBP1, amplifying glycolysis in a feed-forward loop that sustains tumor stem cell properties 2. PFKFB4 is significantly upregulated across multiple malignancies. In breast cancer, PFKFB4–SRC-3 signaling drives metastatic progression and correlates with poor survival in basal-subtype tumors 1. In endometrial cancer, PFKFB4 promotes glycolysis and invasion via SRC-3 phosphorylation, with expression levels correlating with myometrial invasion depth and lymph node metastasis 3. In pancreatic cancer, SP1 transcriptionally activates PFKFB4 to enhance aerobic glycolysis during tumorigenesis 4. In hepatocellular carcinoma, particularly HBV-associated HCC, PFKFB4 upregulation correlates with poor prognosis and promotes lipid synthesis through SREBP1 induction 5. PFKFB4 silencing inhibits cell migration, invasion, and glycolytic capacity across these contexts. Combination therapies targeting SP1 and PFKFB4 show efficacy in pancreatic cancer models, positioning dual glycolytic and transcriptional inhibition as a therapeutic strategy.