UXS1 (UDP-glucuronate decarboxylase 1) catalyzes the NAD-dependent decarboxylation of UDP-glucuronic acid to UDP-xylose, which is essential for glycosaminoglycan biosynthesis 1. The enzyme operates through a two-step mechanism: first oxidizing UDP-glucuronic acid using enzyme-bound NAD+ to produce UDP-4-ketoxylose intermediate, then reducing the 4-keto group to generate UDP-xylose while restoring the NAD+-bound form 1. Beyond its biosynthetic role, UXS1 serves a critical detoxification function by preventing excess accumulation of UDP-glucuronic acid, which can disrupt Golgi morphology and impair receptor trafficking when accumulated 2. This detoxification role creates cancer-specific vulnerabilities, particularly in KEAP1-mutant lung cancers where elevated UGDH expression leads to increased UDP-glucuronic acid production 3. Loss of UXS1 in these cancers causes pyrimidine nucleotide depletion, DNA replication stress, and cell death through UDP sequestration 3. Clinically, UXS1 dependency represents a therapeutic target in cancers with high UGDH expression, including lung adenocarcinoma and gastroesophageal cancer, where UXS1 inhibition selectively affects cancer cells while sparing normal tissue 24. The enzyme also requires metabolic rescue by TGDS-produced UDP-4-keto-6-deoxyglucose in NAD+-scarce environments, with deficiencies linked to Catel-Manzke syndrome 1.