Glycogen branching enzyme 1 as a metabolic determinant and prognostic driver of the CMS4 subtype in colorectal cancer

Colorectal cancer (CRC) continues to impose a substantial global health burden, ranking among the top causes of cancer incidence and mortality. Despite meaningful advances in screening, surgical techniques, and systemic therapy, patients with biologically aggressive molecular subtypes-particularly consensus molecular subtype 4 (CMS4)-experience limited therapeutic benefit and disproportionately poor outcomes. CMS4 tumors are characterized by a mesenchymal phenotype, pronounced hypoxic signaling, activation of Wnt-driven transcriptional programs, and a proliferative state that contributes to treatment resistance. Identifying actionable metabolic determinants of this phenotype remains an unmet clinical need.Through integrative multi-omics profiling across independent CRC cohorts, we identified glycogen branching enzyme 1 (GBE1) as a central metabolic regulator closely aligned with the CMS4 transcriptional landscape. GBE1 expression is significantly enriched in CMS4 tumors and demonstrates a strong, inverse association with overall survival, underscoring its potential as a subtype-specific prognostic biomarker. Transcriptomic analyses further reveal that GBE1 and its downstream glycogen-synthesis pathways are selectively activated in CMS4 tumors, achieving robust statistical significance.Mechanistically, GBE1 operates as a hypoxia-induced effector downstream of HIF-1alpha, reshaping carbohydrate metabolism in a manner that reinforces the metabolic rigidity of CMS4 disease. Beyond its canonical enzymatic role, GBE1 influences broader glycosylation and glycosyltransferase networks, and modulates lipid biosynthetic programs through the PPARgamma/Wnt/beta-catenin axis. This dual control of carbohydrate and lipid metabolism endows CMS4 tumors with a pronounced growth advantage. Functional studies using CRISPR-mediated GBE1 knockout demonstrate marked suppression of tumor cell proliferation and attenuation of Wnt/beta-catenin signaling, confirming its mechanistic role in sustaining the pro-invasive CMS4 phenotype.Together, these findings identify GBE1 as a clinically meaningful metabolic vulnerability that defines the CMS4 subtype. GBE1 emerges as both a prognostic marker and a tractable therapeutic target, providing a precision oncology framework for the management of high-risk CRC patients with metabolically and immunologically dysregulated diseases.