Targeting phosphofructokinase in cancer: integrating natural products for metabolic reprogramming and therapeutic innovation

The metabolism of cancer cells is reprogrammed toward aerobic glycolysis (the Warburg effect), which stimulates tumor growth. Phosphofructokinase (PFK) and its isoforms, PFKP, PFKM, and PFKL, are highly conserved central glycolytic controllers and a potential therapeutic intervention. This review discusses the complex functions of PFK in tumor biology, including its roles in regulating proliferation, invasion, metastasis, and therapy resistance. It further discusses the tumor microenvironmental role of PFK, which influences immune evasion, angiogenesis, and stromal interactions, as well as its non-metabolic signaling functions. The therapeutic approaches to PFK, such as synthetic (e.g., PFK15) and natural (e.g., curcumin) compounds, are considered alongside strategies to address specific difficulties. Lastly, the review is based on a combination of expression analysis of PFK isoforms and a closer analysis of synthetic and natural inhibitors, and it suggests a prospective framework for implementing PFK-targeted therapies in clinical practice that incorporates AI-based drug design, nanodelivery, and immune-metabolic modulation.