Pfkfb3, also known as 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3, is a key glycolytic enzyme. It produces fructose-2,6-biphosphate (F2,6BP), which activates 6-phosphofructo-1-kinase (PFK-1) in glycolysis. Glycolysis is crucial for energy production and various cellular functions, and Pfkfb3-mediated glycolysis is involved in multiple biological processes and disease-related pathways [2,3,10]. Genetic models, such as KO/CKO mouse models, are valuable for studying its functions.

In kidney fibrosis, PTC-specific deletion of Pfkfb3 in mice reduced kidney lactate levels, mitigated inflammation and fibrosis, and preserved kidney function after ischemia-reperfusion injury, suggesting its role in promoting kidney fibrosis through histone lactylation-mediated NF-κB family activation [1]. In sepsis, inhibition of Pfkfb3 alone or in combination showed potential in treatment as sepsis-induced high expression of Pfkfb3 in cells enhanced glycolytic flux and was related to excessive inflammation and high mortality [2]. In vessel sprouting, loss of Pfkfb3 in endothelial cells impaired vessel formation, regulating EC proliferation, filopodia/lamellipodia formation, and directional migration [3]. In endothelial-to-mesenchymal transition (EndoMT) and cardiac fibrosis, pharmacological suppression or haplodeficiency of Pfkfb3 attenuated EndoMT and fibrotic response [4]. In pulmonary hypertension, heterozygous global deficiency or endothelial-specific deficiency of Pfkfb3 in mice protected them from developing or slowed the progression of hypoxia-induced PH [5]. In diabetic retinopathy, the HIF1α-Pfkfb3 pathway is implicated in pathologic angiogenesis and neurodegeneration [6]. In pulmonary arterial hypertension, inhibition of Pfkfb3 in smooth muscle attenuated vascular remodeling [7]. In small cell lung carcinoma, inhibition of Pfkfb3 reduced glycolysis, proliferation, and the expression of cancer stem cell markers [8]. In acute lung injury in sepsis, endothelial-specific knockout of Pfkfb3 in mice reduced endothelium permeability, pulmonary edema, and improved survival rate [9].

In conclusion, Pfkfb3-driven glycolysis is essential in multiple biological processes. Studies using KO/CKO mouse models have revealed its significant roles in diseases such as kidney fibrosis, sepsis, various cardiovascular and pulmonary diseases, diabetic retinopathy, and cancer. Understanding Pfkfb3 functions provides potential therapeutic targets for these disease areas.