Fisetin Induces Apoptosis and Inhibits Migration of Melanoma Cells by Suppressing Glycolytic Metabolism via PKM2 Inhibition

Melanoma is one of the most aggressive forms of skin cancer, often exhibiting resistance to conventional therapies and a high rate of metastasis 1,2 .The Warburg effect, a hallmark of cancer metabolism, is characterized by increased glycolysis even under normoxic conditions, facilitating rapid energy production and biosynthesis in tumor cells 3 .Pyruvate kinase M2 (PKM2) is a key enzyme that catalyzes the final step of glycolysis and is predominantly expressed in proliferating cancer cells, including melanoma 4 .Beyond its metabolic role, PKM2 also modulates gene expression and cell signaling pathways, contributing to tumor growth and metastasis 4,5 .Given this central role, PKM2 is considered a promising therapeutic target for metabolic intervention in cancer 4,5 .Fisetin (3,3',4',7-tetrahydroxyflavone) is a naturally occurring flavonoid found in various fruits and vegetables with reported anti-inflammatory, antioxidant, and anticancer properties (Fig. 1A).Previous studies have demonstrated that fisetin can inhibit proliferation, induce apoptosis, and modulate signaling pathways, including PI3K/Akt and MAPK, in various cancer types 6 .However, the specific metabolic effects of fisetin, especially its impact on glycolysis and PKM2 activity in melanoma cells, remain poorly understood.In this study, we investigated the expression level of PKM2 in human melanoma tissue and explored the anticancer effects of fisetin against melanoma through PKM2mediated glycolytic metabolism.PKM2 expression level was analyzed in 6 malignant melanoma tissues and 6 matched normal skin tissues ex vivo.Details about the materials and methods are provided in the Supplementary Data 1.Western blot analysis revealed significantly higher expression of PKM2 proteins in all melanoma tissues vs. normal skin tissues (Fig. 1B).The relative protein expressions were statistically significant (Mann-Whitney U test, p