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, playing a crucial role in metabolic reprogramming. Its activity is involved in multiple signaling pathways and is important for various biological processes such as cell proliferation, DNA repair, and drug resistance [6]. Genetic models like 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, indicating its role in driving kidney fibrosis through promoting 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, related to excessive inflammation and high mortality [2]. In vessel sprouting, loss of Pfkfb3 in endothelial cells impaired vessel formation [3]. In endothelial-to-mesenchymal transition and fibrotic response, pharmacological suppression or haplodeficiency of Pfkfb3 attenuated these processes [4]. In pulmonary hypertension, heterozygous global deficiency or endothelial-specific deficiency of Pfkfb3 in mice protected them from developing or slowed the progression of PH [5].

In conclusion, Pfkfb3 is essential in regulating glycolysis and has significant impacts on multiple biological processes. Studies using KO/CKO mouse models have revealed its roles in diseases such as kidney fibrosis, sepsis, and pulmonary hypertension, providing potential therapeutic targets for these conditions.

References:

1. Wang, Yating, Li, Hongyu, Jiang, Simin, Liu, Qinghua, Mao, Haiping. 2024. The glycolytic enzyme PFKFB3 drives kidney fibrosis through promoting histone lactylation-mediated NF-κB family activation. In Kidney international, 106, 226-240. doi:10.1016/j.kint.2024.04.016. https://pubmed.ncbi.nlm.nih.gov/38789037/

2. Xiao, Min, Liu, Dadong, Xu, Yao, Mao, Wenjian, Li, Weiqin. . Role of PFKFB3-driven glycolysis in sepsis. In Annals of medicine, 55, 1278-1289. doi:10.1080/07853890.2023.2191217. https://pubmed.ncbi.nlm.nih.gov/37199341/

3. De Bock, Katrien, Georgiadou, Maria, Schoors, Sandra, Dewerchin, Mieke, Carmeliet, Peter. . Role of PFKFB3-driven glycolysis in vessel sprouting. In Cell, 154, 651-63. doi:10.1016/j.cell.2013.06.037. https://pubmed.ncbi.nlm.nih.gov/23911327/

4. Zeng, Hao, Pan, Ting, Zhan, Meiling, Yang, Hua, Li, Ping. 2022. Suppression of PFKFB3-driven glycolysis restrains endothelial-to-mesenchymal transition and fibrotic response. In Signal transduction and targeted therapy, 7, 303. doi:10.1038/s41392-022-01097-6. https://pubmed.ncbi.nlm.nih.gov/36045132/

5. Cao, Yapeng, Zhang, Xiaoyu, Wang, Lina, Su, Yunchao, Huo, Yuqing. 2019. PFKFB3-mediated endothelial glycolysis promotes pulmonary hypertension. In Proceedings of the National Academy of Sciences of the United States of America, 116, 13394-13403. doi:10.1073/pnas.1821401116. https://pubmed.ncbi.nlm.nih.gov/31213542/

6. Galindo, Claudia Martins, Oliveira Ganzella, Fernando Augusto de, Klassen, Giseli, Souza Ramos, Edneia Amancio de, Acco, Alexandra. 2022. Nuances of PFKFB3 Signaling in Breast Cancer. In Clinical breast cancer, 22, e604-e614. doi:10.1016/j.clbc.2022.01.002. https://pubmed.ncbi.nlm.nih.gov/35135735/