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Metabolic enzyme-associated protein-protein interactions (mPPIs) in cancer: potential vulnerability for cancer treatment?

Acta Pharmacologica Sinica (2025)Cite this article

Abstract

Cancer metastasis and drug resistance are intricately linked processes that drive cancer progression and poor prognosis. One of the hallmarks of cancer is metabolic reprogramming, which evolves at various stages of tumor metastasis and drug resistance progression. This reprogramming involves the dysregulation of metabolic enzymes, which not only regulate the metabolic status in cancer cells, but also play multifunctional roles through influencing downstream signaling networks, acting as protein kinases, post-translational modifications and multiple biological processes, thereby exacerbating cancer malignancy. This review focuses on the metabolic enzyme-associated protein-protein interactions (mPPIs) during tumor metastasis and therapeutic resistance, and discusses the roles of key enzymes in glycolysis, the serine synthesis pathway, the pentose phosphate pathway, the glucuronate pathway and the sorbitol pathway. Understanding the distinct multifunctionality of these metabolic enzymes is crucial for gaining valuable insights into cancer pathogenesis and identifying potential therapeutic vulnerability to combat metastatic progression and overcome therapy resistance.

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Fig. 1: Key metabolic enzymes harboring metabolic enzyme-associated protein-protein interactions (mPPIs) in glucose metabolism.
Fig. 2: mPPIs of hexokinase (HK), glucose 6-phosphate isomerase (GPI) and phosphofructokinase 1 (PFK1).
Fig. 3: mPPIs of aldolase A (ALDOA), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and phosphoglycerate kinase 1 (PGK1).
Fig. 4: mPPIs of phosphoglycerate kinase 1 (PGAM1), enolase (ENO) and lactate dehydrogenase A (LDHA).
Fig. 5: mPPIs of pyruvate kinase M2 (PKM2).
Fig. 6: Serine synthesis pathway (SSP) enzymes promote tumor development via mPPIs.
Fig. 7: mPPIs of metabolic enzymes in the sorbitol pathway, pentose phosphate pathway and glucuronate pathway.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (82473936 and 82073868). Owing to space limitation, we regret omitting citations of papers that have contributed to the field.

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  1. These authors contributed equally: Yu-ting Tang, Tian-yi Chen, Zi-yi Liu

Authors and Affiliations

  1. Department of Pharmacology and Chemical Biology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Yu-ting Tang, Tian-yi Chen, Zi-yi Liu, Ming-yu Luo, Miao-miao Gong & Ying Shen

  2. Collaborative Innovation Center for Clinical and Translational Science by Chinese Ministry of Education & Shanghai, Shanghai, 200025, China

    Yu-ting Tang, Tian-yi Chen, Zi-yi Liu, Ming-yu Luo, Miao-miao Gong & Ying Shen

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  1. Yu-ting Tang
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Tang, Yt., Chen, Ty., Liu, Zy. et al. Metabolic enzyme-associated protein-protein interactions (mPPIs) in cancer: potential vulnerability for cancer treatment?. Acta Pharmacol Sin (2025). https://doi.org/10.1038/s41401-025-01601-y

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