Abstract 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-1α, 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 PPARγ/Wnt/β-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/β-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. Citation Format: Fang-Chi Hsu, Leila Su, Frank Luh, Yi-Fan Chen, Xin Wang, Yun Yen. Glycogen branching enzyme 1 as a metabolic determinant and prognostic driver of the CMS4 subtype in colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7728.
Hsu et al. (Fri,) studied this question.