The pivotal role of SFRP2 in promoting glycolysis and progression in the high-risk group based on the glycometabolism prognostic model for colorectal cancer.

Background: Reprogramming glucose metabolism is a hallmark of human cancer during its occurrence and development. However, the comprehensive glycometabolism signature and underlying mechanism in CRC prognosis and immune response remind to be elucidated.

Methods: A prognostic model derived from 297 glycometabolism-related genes (GRGs) was developed using LASSO-Cox and nomogram algorithms. Immune dysfunction between high-risk (Risk^H) and low-risk (Risk^L) groups was compared using CIBERSORT, TIMER, and TIDE analyses. The expression and function of key genes, including secreted frizzled-related protein 2 (SFRP2), were validated using PCR, western blotting, immunohistochemistry, transwell assays, and metastatic model in mice. Luciferase reporter and chromatin immunoprecipitation were used to determine the transcription regulation of ENO2 by TCF4.

Results: More than half of the GRGs (152 out of 297) showed differential expression, mainly those associated with glycolysis and biosynthesis. The GRG-risk score outperformed other clinical indicators (AUC = 0.810) and served as an independent risk predictor (P < 0.001, HR = 3.180). The Risk^H group showed increased infiltration of immune cells and higher immune checkpoint expression. Mechanistically, SFRP2, a key gene in Risk^H, promoted CRC glycolysis and metastasis via enolase 2 (ENO2) activation through the TCF4/β-catenin axis. Inhibiting ENO2 reversed SFRP2-induced metastasis. Coexpression of SFRP2 and ENO2 correlated with poorer survival and higher recurrence.

Conclusion: The Risk^H group is characterized by glycolysis overactivation and immune exclusion. SFRP2 and ENO2 have emerged as promising treatment targets for high-risk CRC patients.