Gastric cancer (GC) is a major cause of morbidity and mortality worldwide; despite recent therapeutic advances, overall prognosis remains dismal due to late-stage diagnosis and therapeutic resistance. Among emerging mechanisms underlying tumor progression and therapeutic vulnerability, ferroptosis is defined as an iron-dependent form of regulated cell death that is characterised by the process of lipid peroxidation, has been increasingly implicated in the initiation and progression of diverse malignancies, including gastric cancer. In parallel, metabolic reprogramming has been recognized as a hallmark of cancer, with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) gaining attention as a key bifunctional metabolic enzyme. By modulating intracellular levels of fructose-2,6-bisphosphate, PFKFB4 orchestrates the balance between glycolysis and the pentose phosphate pathway (PPP), thereby supporting redox homeostasis and anabolic growth. Notably, recent studies have identified aberrant overexpression of PFKFB4 in a range of malignancies, implicating it in tumor progression. Building on this, in the present study, we demonstrated that PFKFB4 is markedly overexpressed in GC cells and modulates their sensitivity to ferroptosis through direct interaction with, and phosphorylation of, Heat Shock Protein Beta-1 (HSPB1), a critical negative regulator of ferroptotic signaling. Importantly, treatment with 5MPN, a specific inhibitor of PFKFB4, significantly potentiates ferroptotic cell death and suppresses GC tumor growth. These findings identify a previously unrecognized function of PFKFB4 in GC, extending beyond its canonical metabolic roles to include active regulation of ferroptosis, thereby promoting cancer progression. Consequently, pharmacological inhibition of PFKFB4 represents a promising therapeutic avenue for overcoming ferroptosis resistance and suppressing tumor progression in gastric cancer.
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