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<p>Colorectal cancer (CRC) is the third most common malignant tumor worldwide, while its underlying pathogenic mechanisms remain inadequately understood. Glycolysis reprogramming represents a key metabolic hallmark of CRC, the mechanism of which needs to be further clarified. We have reported that the glycolytic enzyme PGK1, working as a kinase, interacts with and phosphorylates PRAS40 to promote hepatocellular carcinoma development. However, the role of PRAS40 in regulating PGK1 function and glycolysis is unclear. Our findings identify the overexpression of PRAS40 in CRC tissues and demonstrate that its genetic deletion potently inhibits tumorigenesis in murine models. The following functional analyses reveal that PRAS40 contributes to both cell growth and lactate production. Mechanistically, PRAS40 serves as a scaffold protein, associates with and promotes the interaction of three critical glycolytic enzymes-G6PI, PGK1, and LDHA, constructing an efficient functional enzyme complex. Consequently, PRAS40 enhances the activity of these enzymes. These findings indicate that PRAS40 accelerates glycolysis by facilitating the assembly of the G6PI/PGK1/LDHA enzyme complex, thereby contributing to CRC tumorigenesis. These insights may provide novel therapeutic strategies for the treatment of CRC.</p>

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PRAS40 enhances glycolysis by facilitating G6PI/PGK1/LDHA complex assembly in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月19日

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  • Tianhua Zhang,
  • Chengfei Zhang,
  • Yukun Hao,
  • Ting Zhang,
  • Lin Huang

摘要

Colorectal cancer (CRC) is the third most common malignant tumor worldwide, while its underlying pathogenic mechanisms remain inadequately understood. Glycolysis reprogramming represents a key metabolic hallmark of CRC, the mechanism of which needs to be further clarified. We have reported that the glycolytic enzyme PGK1, working as a kinase, interacts with and phosphorylates PRAS40 to promote hepatocellular carcinoma development. However, the role of PRAS40 in regulating PGK1 function and glycolysis is unclear. Our findings identify the overexpression of PRAS40 in CRC tissues and demonstrate that its genetic deletion potently inhibits tumorigenesis in murine models. The following functional analyses reveal that PRAS40 contributes to both cell growth and lactate production. Mechanistically, PRAS40 serves as a scaffold protein, associates with and promotes the interaction of three critical glycolytic enzymes-G6PI, PGK1, and LDHA, constructing an efficient functional enzyme complex. Consequently, PRAS40 enhances the activity of these enzymes. These findings indicate that PRAS40 accelerates glycolysis by facilitating the assembly of the G6PI/PGK1/LDHA enzyme complex, thereby contributing to CRC tumorigenesis. These insights may provide novel therapeutic strategies for the treatment of CRC.