P06.08 Targeting UXS1 to suppress colorectal cancer progression by regulating glycan biosynthesis, metabolic reprogramming, and immune evasion

Background Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with recurrence and metastasis posing major therapeutic challenges. UDP-xylose synthase 1 (UXS1) generates UDP-xylose required for initiation of glycosaminoglycan (GAG) biosynthesis, yet its role in CRC progression is poorly understood.Material and methods Public transcriptomic datasets were analyzed to assess UXS1 expression and clinical relevance. Genetic ablation of UXS1 was performed using knockout or knockdown approaches in colon cancer cell lines. Metabolic profiling, cell surface GAG analysis, RNA sequencing, and ferroptosis assays were conducted. Tumor growth and immune infiltration were evaluated in syngeneic mouse models. Structure-based molecular docking was used to identify candidate UXS1 inhibitors.Results UXS1 expression was elevated in CRC tissues and associated with poor patient prognosis. UXS1 knockout or knockdown impaired colon cancer cell viability and invasiveness, independent of UDP-glucose dehydrogenase expression. Mechanistically, loss of UXS1 reduced cell surface GAG levels, suppressed glycolytic and tricarboxylic acid cycle activity, and increased ferroptosis, consistent with RNA sequencing analyses. In syngeneic models, Uxs1 knockout markedly inhibited tumor growth in CT26 tumors. Notably, Uxs1-deficient CT26 tumors displayed increased leukocyte infiltration, indicating a previously unrecognized immunomodulatory function. Molecular docking identified pemetrexed as a putative UXS1 inhibitor, and pemetrexed treatment reduced cell surface GAG expression, supporting direct pharmacologic targeting of UXS1.Conclusions These findings suggest that altered glycan biosynthesis, metabolic reprogramming, and immune suppression collectively contribute to UXS1-mediated colorectal cancer progression and establish UXS1 as a promising therapeutic target.