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

IF 6.1 2区生物学 Q1 CELL BIOLOGY

Cell Death Discovery Pub Date : 2025-07-14 DOI:10.1038/s41420-025-02623-5

Boran Pang, Hao Wu

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Abstract

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.

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结直肠癌的代谢重编程：有氧糖酵解及其对靶向治疗策略的治疗意义的综述。

结直肠癌（CRC）仍然是一个重大的肿瘤学挑战，是全球癌症相关死亡率的主要贡献者之一。这篇综述总结了我们目前关于代谢重编程，特别是Warburg效应如何促进结直肠癌病理生物学的知识，并探讨了其治疗相关性。CRC代谢重编程的特点是从氧化磷酸化到糖酵解的转变，称为Warburg效应。在肿瘤微环境（TME）的驱动下，这种适应通过加速ATP生成、生物合成支持和氧化还原平衡来增强癌细胞增殖。关键的糖酵解酶，即己糖激酶、磷酸果糖激酶、丙酮酸激酶和乳酸脱氢酶，现在是CRC治疗策略的优先治疗靶点。利用CRC代谢改变的诊断方法，如18f -氟脱氧葡萄糖正电子发射断层扫描（18F-FDG PET/CT）和循环代谢物的代谢组学分析，通过提高灵敏度和特异性，改善了早期检测。这些方法揭示了结直肠癌独特的代谢特征，从而实现了精确的疾病分层和管理。针对EMP通路的治疗策略在克服crc相关的化疗耐药和放射耐药方面显示出临床前疗效。调节emp调节通路（AKT， AMPK, mTOR）提供了额外的治疗机会。然而，CRC的代谢异质性需要多目标的方法。靶向治疗的发展必须考虑到对依赖EMP的正常组织的潜在脱靶效应，需要在治疗效果和安全性之间取得谨慎的平衡。总之，这篇综述强调了CRC中代谢重编程的复杂性，以及对有效靶向这些途径的细致方法的需求。后续研究应优先确定肿瘤选择性代谢脆弱性，并设计多途径干预措施，避免正常组织，最终提高结直肠癌管理的治疗精度。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Death Discovery Biochemistry, Genetics and Molecular Biology-Cell Biology

CiteScore

8.30

自引率

1.40%

发文量

468

审稿时长

9 weeks

期刊介绍： Cell Death Discovery is a multidisciplinary, international, online-only, open access journal, dedicated to publishing research at the intersection of medicine with biochemistry, pharmacology, immunology, cell biology and cell death, provided it is scientifically sound. The unrestricted access to research findings in Cell Death Discovery will foster a dynamic and highly productive dialogue between basic scientists and clinicians, as well as researchers in industry with a focus on cancer, neurobiology and inflammation research. As an official journal of the Cell Death Differentiation Association (ADMC), Cell Death Discovery will build upon the success of Cell Death & Differentiation and Cell Death & Disease in publishing important peer-reviewed original research, timely reviews and editorial commentary. Cell Death Discovery is committed to increasing the reproducibility of research. To this end, in conjunction with its sister journals Cell Death & Differentiation and Cell Death & Disease, Cell Death Discovery provides a unique forum for scientists as well as clinicians and members of the pharmaceutical and biotechnical industry. It is committed to the rapid publication of high quality original papers that relate to these subjects, together with topical, usually solicited, reviews, editorial correspondence and occasional commentaries on controversial and scientifically informative issues.