{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPhosphofructokinase-1 liver type (PFKL) is a pivotal glycolytic enzyme whose regulation is critical for cellular energy balance and metabolic reprogramming in cancer. In tumor cells, for instance, modification by O‑GlcNAcylation at a specific serine (Ser529) inhibits PFKL activity, thereby rerouting glucose flux from glycolysis toward the pentose phosphate pathway. This metabolic shift supports biosynthesis and antioxidant defense, ultimately conferring a selective growth advantage under hypoxic conditions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nIn immune cells such as neutrophils, PFKL plays an equally strategic role by fine‑tuning energy production. Small‑molecule activators that bind to its AMP/ADP allosteric site enhance PFKL activity, thereby increasing glycolytic throughput and simultaneously reducing flux through the pentose phosphate pathway. This regulation contributes to a controlled NADPH oxidase (NOX2)‑dependent oxidative burst, moderating reactive oxygen species generation and mitigating associated tissue damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nStructurally, PFKL exhibits unique behaviors compared to other PFK isoforms. Under substrate‑rich conditions, recombinant PFKL assembles into dynamic tetrameric filaments, a process that underlies its spatial organization within cells and influences its allosteric regulatory properties. Detailed kinetic studies further reveal that PFKL has distinct substrate affinities and sensitivities to allosteric effectors when compared with platelet and muscle isoforms, while high‑resolution structural analyses have begun to illuminate the conformational changes that govern its active (R‑state) and inhibited (T‑state) forms."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "3", "end_ref": "5"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its catalytic function, the stability and abundance of PFKL are finely controlled by protein quality‐control systems that impact cancer progression. In hepatocellular carcinoma, the E3 ubiquitin ligase A20 promotes PFKL degradation, thereby suppressing glycolytic flux and tumor growth. In contrast, in oral squamous cell carcinoma, the deubiquitinating enzyme USP14 interacts with and stabilizes PFKL, enhancing glycolytic metabolism, cell proliferation, and metastasis. Additionally, interactions with other proteins such as Tiam1 have been shown to further drive metabolic reprogramming in breast cancer via PFKL."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": ""}, {"type": "p", "children": [{"type": "t", "text": "\nTranscriptional regulation also plays a key role in modulating PFKL expression and function. For example, activation by transcription factors such as TAp73 enhances PFKL expression, thereby promoting the Warburg effect, with increased glucose uptake, lactate production, ATP generation, and improved cellular antioxidant capacity. Moreover, altered subcellular localization patterns of PFKL—as observed in ductal carcinoma in situ—may serve as metabolic switches that predict cancer recurrence, providing potential avenues for diagnostic stratification and targeted therapy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}]}]}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wen Yi, Peter M Clark, Daniel E Mason, et al. 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