Targeting glycolysis in prostate cancer: Molecular mechanisms and therapeutic advances

Prostate cancer (PCa) is the second most common cancer among men worldwide and poses a significant threat to male health. A key feature of tumor progression is metabolic reprogramming, which involves the abnormal activation of glycolysis. This metabolic process supports PCa proliferation, metastasis, and drug resistance through rapid energy production, the provision of biosynthetic precursors, and the remodeling of the tumor microenvironment (TME). Key enzymes such as hexokinase 2 (HK2), phosphofructokinase (PFK), pyruvate kinase M2 (PKM2), glucose transporters (GLUTs), and lactate dehydrogenase A (LDHA) play pivotal roles in regulating aerobic glycolysis in PCa cells. Glycolytic enzymes are modulated by a variety of mechanisms, including the PI3K/AKT and AMPK signaling pathways, hypoxia-inducible factor 1α (HIF-1α), c-Myc, and non-coding RNAs. Current therapeutic strategies targeting glycolysis include natural products and small-molecule inhibitors. Targeting glycolysis presents novel opportunities to address existing limitations in PCa management. This review discusses the advances, challenges, and future research directions in glycolysis-focused PCa studies, providing a theoretical foundation for the development of precise metabolic interventions.