Metabolic reprogramming in colorectal cancer: a review of aerobic glycolysis and its therapeutic implications for targeted treatment strategies.

Colorectal cancer (CRC) remains a significant oncological challenge, being among the foremost contributors to cancer-related mortality worldwide. This review summarizes our current knowledge regarding how metabolic reprogramming, specifically the Warburg effect, contributes to CRC pathobiology and explores its therapeutic relevance. Metabolic reprogramming in CRC is characterized by a shift from oxidative phosphorylation to glycolysis, termed the Warburg effect. Driven by the tumor microenvironment (TME), this adaptation enhances cancer cell proliferation through accelerated ATP generation, biosynthesis support, and redox balance. Key glycolytic enzymes, namely hexokinase, phosphofructokinase, pyruvate kinase, and lactate dehydrogenase are now prioritized as therapeutic targets in CRC treatment strategies. Diagnostic modalities utilizing CRC's altered metabolism such as 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT) and metabolomic analysis of circulating metabolites, improved early detection through enhanced sensitivity and specificity. These approaches reveal CRC's distinct metabolic signatures, enabling precise disease stratification and management. Therapeutic strategies targeting the EMP pathway show preclinical efficacy in overcoming CRC-associated chemoresistance and radioresistance. Modulation of EMP-regulating pathways (AKT, AMPK, mTOR) provides additional therapeutic opportunities. However, CRC's metabolic heterogeneity demands multi-targeted approaches. The development of targeted therapies must consider the potential off-target effects on normal tissues that rely on EMP, necessitating a careful balance between therapeutic efficacy and safety. In summary, this review underscores the complexity of metabolic reprogramming in CRC and the need for a nuanced approach to target these pathways effectively. Subsequent investigations should prioritize defining tumor-selective metabolic vulnerabilities and engineering multi-pathway interventions that spare normal tissues, ultimately advancing therapeutic precision in CRC management.