Molecular mechanisms and targeted therapeutic strategies for glycolytic reprogramming in osteosarcoma

Osteosarcoma, a highly invasive and metastatic malignant bone tumor, has a poor prognosis primarily because of early pulmonary metastasis and resistance to conventional treatments. The malignant progression of osteosarcoma cells significantly depends on glycometabolic reprogramming, a process characterized by enhanced aerobic glycolysis. This review begins by mapping the multi-dimensional networks driving sugar metabolism reprogramming, which revealed that functional abnormalities in core glycolytic enzymes, including hexokinase 2, pyruvate kinase M2, and lactate dehydrogenase A (LDHA), are driven by a multi-level regulatory network that includes altered transcription factor activity, epigenetic modifications, and interactions mediated by non-coding RNAs. Mitochondrial dysfunction leads to succinate and reactive oxygen species accumulation, synergistically promoting the remodeling of metabolic pathways. Furthermore, the synergistic interaction between the pentose phosphate pathway and glutamine metabolism accelerates the energy supply and biosynthesis, whereas lactate accumulation shapes the immunosuppressive microenvironment by inhibiting immune cell function. This review focuses on dissecting the core mechanisms of glucose metabolism reprogramming in osteosarcoma pathogenesis, including promoting proliferation, inhibiting apoptosis, enhancing invasion and metastasis, regulating immune metabolism, and mediating chemotherapy resistance. Additionally, it evaluates novel therapeutic strategies targeting key nodes of glucose metabolism in osteosarcoma, including advances in preclinical research on specific small-molecule inhibitors and gene regulatory approaches. Finally, it delves into the major challenges in translational research, such as metabolic heterogeneity, targeting selectivity, and compensatory resistance, as well as prospects for future research, including multi-omics analysis, smart delivery systems, organoid models, and combination immunotherapy. This study offers novel insights into overcoming the therapeutic bottlenecks in osteosarcoma treatment.