{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPFKFB4 is a bifunctional enzyme that plays a central role in regulating glycolytic flux by controlling the cellular levels of fructose-2,6-bisphosphate, a key allosteric activator of phosphofructokinase-1. Its expression is frequently up‐regulated in cancer cells as well as under hypoxic conditions through HIF‐dependent mechanisms, and it can modulate transcriptional programs by phosphorylating transcriptional coactivators (for example, SRC-3) to rewire glucose metabolism toward anabolic pathways such as the pentose phosphate pathway and nucleotide biosynthesis. In p53-deficient cells, PFKFB4 becomes even more essential for balancing glycolysis and antioxidant production, thereby ensuring survival under metabolic stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn diverse cancer types—including breast, prostate, glioblastoma, bladder, lung, and melanoma—PFKFB4 has been implicated in promoting aggressive neoplastic behaviors. It supports oncogenic processes by enhancing cell survival, stemness, chemoresistance and metastatic potential through multiple mechanisms. For instance, its transcription can be upregulated by factors such as CD44 intracellular domain and PPARγ or de-repressed by the loss of p53, while its activity is modulated through protein–protein interactions (with kinases like Etk) and by regulatory noncoding RNAs. Its elevated activity drives glycolysis and anabolism, thereby facilitating tumor progression, invasion and even resistance to chemotherapeutic agents."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its central role in cancer metabolism, PFKFB4 also represents a promising therapeutic and prognostic target. Inhibition of its kinase activity using agents such as 5MPN has been shown to reduce glycolytic flux, lower ATP production and suppress tumor growth in preclinical models of several malignancies, including oral squamous cell carcinoma and non‐small cell lung cancer where microRNAs (e.g. miR‑3195 and miR‑195‑5p) can modulate its expression. Notably, complexes involving transcription regulators (for example, FBL/KHSRP or THOC3/YBX1) further underscore its role in tumor progression in liver and lung cancers. Moreover, aberrant PFKFB4 levels have been detected not only in pediatric gliomas and triple‑negative breast cancers but also in non-malignant disorders such as fibrous dysplasia, endometriosis, and even in metabolic alterations seen in pre‑eclampsia and hypoxic tissues—highlighting its broader significance in pathophysiologic metabolic reprogramming."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Subhamoy Dasgupta, Kimal Rajapakshe, Bokai Zhu, et al. 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