Breaking the metabolic code in triple-negative breast cancer: Mechanistic insights into glycolytic enzyme inhibitors for suppressing metastasis and tumor growth

Triple-negative breast cancer (TNBC) is an aggressive and metastatic form of breast cancer with limited treatment options. Glycolytic enzymes such as hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) serve as effective targets for metabolic reprogramming in suppressing tumor growth. This study investigates the effects of glycolytic enzyme inhibitors, particularly phytochemicals, on TNBC metastasis and tumor growth using a 7,12-dimethylbenz(a)anthracene (DMBA)-induced rat model. Following TNBC induction, these rats were treated with phytochemical inhibitors: 2-deoxy-D-glucose (2-DG), shikonin, oxamate, kaempferol, quercetin, or luteolin. Molecular docking analysis was conducted to characterize the interactions between these compounds and the glycolytic enzymes HK2, PKM2, and LDHA. Glycolytic enzyme inhibition was inferred from the protein expression levels of HK2, PKM2, and LDHA in different treatment groups. Among the compounds tested, kaempferol showed the highest binding affinity toward glycolytic enzymes HK2 and PKM. In addition, shikonin and kaempferol exhibited cell-line-specific antiglycolytic properties by inhibiting glycolytic enzymes HK2, PKM2, and LDHA, thereby suppressing TNBC growth and metastasis. These results suggest that glycolytic enzymes could serve as potential therapeutic targets for improving TNBC treatment, with possible clinical application alongside primary conventional therapies.