GUDCA drives colorectal cancer progression via ALKBH5-mediated m6A modification of ENO1 and glycolytic reprogramming.

Colorectal cancer (CRC) is the third most diagnosed malignancy worldwide, yet the mechanisms by which bile acids drive metabolic reprogramming remain unclear. This study investigates whether glycoursodeoxycholic acid (GUDCA) promotes CRC progression through mA epitranscriptomic regulation. Serum bile acids were profiled in 106 CRC patients and 106 controls by UHPLC-MS/MS. Cellular phenotypes were assessed by CCK-8, colony formation, and xenograft models. mA modification was mapped by meRIP-seq and validated by meRIP-qPCR. Glycolytic function was measured by lactate production, glucose uptake, and ECAR. FXR binding to the ALKBH5 promoter was assessed by luciferase assay and ChIP-qPCR. Clinical correlations were analyzed in 25 CRC patients undergoing 1F-FDG-PET. GUDCA was the most significantly elevated bile acid in CRC patients and independently predicted poor survival (HR = 3.28, p < 0.001). GUDCA promoted CRC cell proliferation and xenograft tumor growth. Mechanistically, GUDCA antagonized FXR to suppress ALKBH5 transcription, elevating mA modification of ENO1 mRNA and enhancing its translation efficiency. ALKBH5 deficiency drove glycolytic reprogramming and mTORC1 activation. ENO1 silencing abolished GUDCA-induced glycolytic enhancement. Serum GUDCA positively correlated with 1F-FDG-PET SUVmax (r = 0.68, p < 0.001). Low ALKBH5 expression correlated with poor patient survival. GUDCA functions as an oncometabolite that drives CRC progression via the GUDCA-FXR-ALKBH5-ENO1 axis, establishing a feed-forward metabolic circuit linking bile acid signaling to mA-mediated glycolytic reprogramming. These findings identify GUDCA and ALKBH5 as potential therapeutic vulnerabilities in CRC.