Pfkfb4, or 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4, is a key regulator of glycolysis, possessing both kinase and phosphatase functions. It is involved in the Warburg effect, which provides the metabolic basis for cancer cell proliferation and metastasis [1-10]. Genetic models, such as gene knockout (KO) mouse models, can be valuable for studying its functions.

In lung squamous cell carcinoma, THOC3 can form a complex with YBX1 to promote PFKFB4 transcription, with THOC3 responsible for exporting PFKFB4 mRNA to the cytoplasm and YBX1 ensuring its stability. Down-regulation of PFKFB4 suppressed the biological activities of the cancer cells [1].

In hepatocellular carcinoma (HCC), PFKFB4 expression was up-regulated, correlating positively with TP53 and TSC2 loss-of-function mutations. Nuclease technology-mediated PFKFB4 knockout significantly impaired in vivo HCC development, and its loss induced hypoxia-responsive genes in glycolysis and reactive oxygen species detoxification [2].

In glioma stem cells, PTBP1 lactylation enhanced RNA-binding capacity and facilitated PFKFB4 mRNA stabilization, increasing glycolysis and promoting glioma progression [3].

In endometriosis, PIM2 phosphorylated PFKFB4 at Thr140, promoting anaerobic glycolysis and cell proliferation [4].

In glioblastoma, PFKFB4 was essential for glioblastoma stem-like cell survival, regulating the ubiquitylation and proteasomal degradation of HIF-1α [5].

In melanoma, PFKFB4 interacted with ICMT, activating RAS/AKT-signaling-dependent cell migration [6].

In cervical cancer, PFKFB4 was abnormally increased, boosting the malignant progression of the cancer cells [7].

In breast cancer, PFKFB4 promoted angiogenesis via IL-6/STAT5A/P-STAT5 signaling [8].

In non-small cell lung cancer (NSCLC), PFKFB4 expression was enhanced, and high expression was associated with a worse prognosis, also being related to immune cell infiltration and immunological checkpoints [9].

In conclusion, Pfkfb4 plays a crucial role in glycolysis-related metabolic reprogramming, significantly influencing the development and progression of various cancers, including lung, liver, glioma, endometriosis-associated, glioblastoma, melanoma, cervical, breast, and NSCLC. Studies using KO models have been instrumental in revealing these functions in specific disease contexts, helping to understand the underlying mechanisms and potentially guiding new therapeutic strategies.