Aerobic glycolysis in bladder cancer: research advances and targeted therapy potential

Bladder cancer (BCa) is one of the most common malignant tumors of the urinary system. Its frequent recurrence, high metastatic potential, and resistance to therapies pose major obstacles to achieving long-term patient survival. As a core feature of tumor metabolic reprogramming, aerobic glycolysis (the Warburg effect) plays an essential role in the development of BCa. Current studies indicate that key glycolytic enzymes such as hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), and lactate dehydrogenase A (LDHA) are abnormally expressed in BCa. These alterations in enzyme activity not only directly reshape energy metabolism but also exert non-metabolic functions, regulating tumor cell proliferation and invasion. Simultaneously, the aberrant activation of signaling pathways such as PI3K/AKT/mTOR and HIF-1α further drives the glycolytic process. Moreover, the lactate produced through glycolysis leads to tumor microenvironment (TME) acidification, which facilitates extracellular matrix remodeling and immune evasion. In terms of treatment, strategies that directly target key glycolytic enzymes and indirectly intervene in the regulation of signaling pathways show promising application potential. Nevertheless, issues related to treatment-associated toxicity and the emergence of therapeutic resistance remain unresolved. This review systematically summarizes the characteristics of key enzymes in aerobic glycolysis, molecular regulatory mechanisms, and advancements in targeted therapy for BCa, aiming to provide new theoretical insights and directions for metabolic intervention and targeted therapy in BCa.