大肠癌癌症中的己糖胺生物合成途径：目前的见解和治疗机会

摘要(中文译文)

结直肠癌（CRC）是一种常见的恶性肿瘤，其特征是显著的代谢改变，这些改变驱动肿瘤进展和治疗耐药。己糖胺生物合成途径（HBP）作为一个关键的营养感知枢纽，通过整合来自葡萄糖、谷氨酰胺、脂肪酸和尿苷的通量来控制蛋白质O-GlcNAc糖基化。该途径的失调通过调节致癌信号级联和代谢可塑性促进结直肠癌的发生。本综述阐明了关键酶的不同作用，包括GFAT、PGM3、UAP1以及O-GlcNAc循环酶OGT和OGA，在发挥致癌作用中的角色。我们详细阐述了异常途径通量和下游O-GlcNAc糖基化如何协调关键恶性表型，如上皮-间质转化、癌症干性维持以及赋予化疗耐药的DNA修复机制。此外，我们重点介绍了将HBP失调与肿瘤微环境（TME）重塑联系起来的新兴证据，特别是其在通过巨噬细胞极化和免疫检查点稳定化促进免疫逃逸中的作用。除机制见解外，本文批判性评估了当前靶向该途径的治疗策略，涵盖新型抑制剂、生物标志物指导的干预措施以及与常规化疗或免疫治疗协同的组合疗法。我们还分析了阻碍临床转化的主要障碍。通过构建这一代谢枢纽的生物学复杂性和治疗机遇，本工作旨在为开发精准有效的代谢干预措施提供转化路线图，以改善难治性结直肠癌的临床管理。

Abstract

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.

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