Hexosamine Biosynthesis Pathway in Colorectal Cancer: Current Insights and Therapeutic Opportunities

Colorectal Cancer (CRC) is a prevalent malignancy characterized by significant metabolic alterations that drive tumor progression and therapy resistance. The Hexosamine Biosynthetic Pathway (HBP) functions as a critical nutrient-sensing hub by integrating fluxes from glucose, glutamine, fatty acids, and uridine to control protein O-GlcNAcylation. Dysregulation of this pathway contributes to CRC oncogenesis through the modulation of oncogenic signaling cascades and metabolic plasticity. This review elucidates the distinct roles of key enzymes, including GFAT, PGM3, UAP1, and the O-GlcNAc cycling enzymes OGT and OGA, in exerting oncogenic roles. We detail how aberrant pathway flux and downstream O-GlcNAcylation orchestrate critical malignant phenotypes such as epithelial-to-mesenchymal transition, maintenance of cancer stemness, and DNA repair mechanisms that confer chemoresistance. Furthermore, we highlight emerging evidence linking dysregulation of the HBP to Tumor Microenvironment (TME) remodeling, specifically its role in promoting immune evasion via macrophage polarization and immune checkpoint stabilization. Beyond mechanistic insights, this article critically evaluates current therapeutic strategies targeting the pathway, ranging from novel inhibitors and interventions guided by biomarkers to combination therapies that synergize with conventional chemotherapy or immunotherapy. We also analyze the major hurdles hindering clinical translation. By framing both the biological complexity and therapeutic opportunities of this metabolic nexus, this work aims to provide a translational roadmap for developing precise and effective metabolic interventions to improve the clinical management of refractory CRC.