Pfkfb4, also known as 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4, is a key bidirectional glycolytic enzyme in the phosphofructokinase-fructose bisphosphatase family, possessing both kinase and phosphatase functions. It is involved in crucial metabolic pathways such as glycolysis and the pentose phosphate pathway, and is of great importance in metabolic reprogramming, which is a recognized cancer hallmark [1]. Genetic models, like knockout (KO) mouse models, are valuable for studying its functions.

In hepatocellular carcinoma (HCC), Pfkfb4 expression was up-regulated and correlated with TP53 and TSC2 loss-of-function mutations. Nuclease technology-mediated Pfkfb4 knockout significantly impaired in vivo HCC development, and its ablation caused metabolite accumulation in downstream glycolysis and the pentose phosphate pathway [1]. In glioma, PTBP1 lactylation enhanced its RNA-binding capacity, facilitating Pfkfb4 mRNA stabilization and increasing glycolysis to promote glioma stem cell maintenance [2]. In endometriosis, PIM2 phosphorylated Pfkfb4 at Thr140, promoting anaerobic glycolysis and cell proliferation [3]. In glioblastoma, Pfkfb4 interacted with FBXO28 to regulate HIF-1α ubiquitylation and proteasomal degradation, promoting HIF-1α signaling [4].

In conclusion, Pfkfb4 is essential in metabolic regulation, especially in glycolysis-related processes. Studies using KO models have revealed its significant roles in various diseases, including cancers like HCC, glioma, glioblastoma, and non-cancerous conditions such as endometriosis. Understanding Pfkfb4 functions through these models provides insights into disease mechanisms and potential therapeutic targets.