PFKFB3 is a key regulatory enzyme that catalyzes both the synthesis and degradation of fructose-2,6-bisphosphate, serving as a critical controller of glycolytic flux 1. The enzyme drives metabolic reprogramming by enhancing glycolysis while compromising mitochondrial respiration, particularly through hijacking glucose flux from the pentose phosphate pathway 2. PFKFB3 functions through multiple signaling pathways, including PI3K-Akt-mTOR activation, and its expression is post-transcriptionally regulated by CPEB4 binding to its 3'-UTR 34. The enzyme plays crucial roles in cellular processes beyond metabolism, regulating endothelial cell migration, filopodia formation, and vessel sprouting by compartmentalizing with F-actin in motile protrusions 5. PFKFB3 is significantly upregulated in various pathological conditions including sepsis, chr10 kidney disease, liver fibrosis, and pulmonary fibrosis 6147. Mechanistically, PFKFB3-driven glycolysis promotes inflammatory responses through histone lactylation-mediated NF-κB activation and facilitates pathological cell differentiation processes like endothelial-to-mesenchymal transition and myofibroblast activation 627. Therapeutic targeting of PFKFB3 with inhibitors shows promise in treating fibrotic diseases, sepsis, and metabolic disorders 81.