Uxs1, or UDP-glucuronate decarboxylase 1, is a Golgi enzyme that converts UDP-glucuronic acid (UDPGA) to UDP-xylose. This conversion is crucial as UDP-xylose is involved in the synthesis of proteoglycans, which play important roles in extracellular matrix formation, cell-cell signaling, and tissue development. The sugar nucleotide biosynthetic pathway in which Uxs1 participates is essential for normal cellular function, and genetic models can help uncover its detailed functions [2,4].

In a laser-induced choroidal neovascularization (CNV) mouse model, a circular RNA derived from the Uxs1 gene (circRNA Uxs1) was found to be upregulated in CNV patient specimens and CNV mouse models. Knockdown of circRNA Uxs1 interrupted endothelial cell tube formation, migration, and proliferation in vitro and alleviated neovascularization in vivo, suggesting that circRNA Uxs1 promotes CNV by sponging miR-335-5p, activating the mTOR/p70 S6k pathway [1].

In zebrafish, homozygous uxs1 mutants lack proteoglycan-rich extracellular matrix in cartilages, showing defective chondrocyte organization and disrupted gene expression related to skeletal development, indicating that Uxs1 activity is essential for skeletal extracellular matrix production and organization [4].

In cancer cells, UXS1 is conditionally essential for cells with high UGDH expression levels. Disrupting UXS1 leads to toxic UDPGA accumulation, which disrupts Golgi function and may be a therapeutic vulnerability [2,5]. In addition, a heterozygous UXS1 variant in humans is associated with short-limbed short stature, and the mutant protein loses its ability to convert UDP-glucuronic acid to UDP-xylose [3].

In conclusion, Uxs1 plays essential roles in multiple biological processes, including extracellular matrix formation, angiogenesis, and skeletal development. Studies using gene-knockout models in mice and zebrafish have revealed its functions in disease-related processes such as CNV and in normal development. In cancer, its role in sugar nucleotide clearance may offer potential therapeutic strategies. Understanding Uxs1's functions provides insights into disease mechanisms and potential treatment targets in conditions like CNV, cancer, and skeletal disorders [1,2,3,4,5].