Phosphofructokinase-1 redefined: a metabolic hub orchestrating cancer hallmarks through multi-dimensional control networks.

Phosphofructokinase-1 (PFK-1), the core rate-limiting enzyme of glycolysis, has transcended its classical metabolic regulatory role and emerged as a multi-dimensional hub in tumour biology. This review systematically delineates the dynamic regulatory networks of PFK-1 isoforms (PFKP, PFKL, PFKM) in cancer: epigenetic remodelling drives tissue-independent expression reprogramming; post-translational modification networks confer metabolic-signalling dual functions; and the dynamic nature of its subcellular localization facilitates noncanonical roles, such as intranuclear transcriptional regulation. These mechanisms collectively orchestrate hallmark oncogenic processes, including tumour proliferation, metastatic invasion, cell death evasion, angiogenesis, immune escape, and metabolic reprogramming. In clinical translation, PFK-1 isoform expression profiles, modification states, and subcellular dynamics exhibit robust correlations with cancer diagnosis, prognosis, and therapeutic response. The isoform-specific modification networks unveil novel targets for developing diagnostic biomarkers and tissue-selective therapeutic strategies. This work not only reestablishes the central role of PFK-1 in tumour metabolic plasticity but also offers a fresh perspective for overcoming cancer treatment challenges.