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) and low-risk (Risk) 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 group showed increased infiltration of immune cells and higher immune checkpoint expression. Mechanistically, SFRP2, a key gene in Risk, 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 group is characterized by glycolysis overactivation and immune exclusion. SFRP2 and ENO2 have emerged as promising treatment targets for high-risk CRC patients.