UOX: Key Urate Oxidase Precursor & Hyperuricemia Therapeutic Target

•  Gene Information: Encoded by the *UOX* gene on chromosome 1p22; silenced as a pseudogene in humans, encodes urate oxidase, a member of the purine degradation enzyme family. 
• Protein Expression: Predominantly synthesized in hepatocytes in functional-UOX species, localized within peroxisomes; catalyzes urate oxidation, with expression modulated by purine load and metabolic stress. 
• Signaling Pathway: Catalyzes conversion of poorly soluble uric acid into soluble allantoin; urate accumulation in UOX-deficient status triggers NLRP3 inflammasome activation, oxidative stress, renal tubular injury and crystal-mediated inflammation; the purine metabolic cascade is regulated by XOR, URAT1, ABCG2 and SGLT2. 
• Therapeutic Inhibition: Recombinant UOX proteins (rasburicase, pegloticase) supplement urate-degrading activity to reduce serum urate, applied for tumor lysis syndrome and refractory gout; UOX gene restoration and UOX-targeted nucleic acid agents are emerging strategies to resolve hyperuricemia, urate nephropathy and gouty arthritis.

•  B-Uox flox, Alb cre mice were obtained by mating B-Uox flox mice and Alb cre mice.
•  Cre recombinase is expressed specifically in hepatocytes driven by Alb promoter, mediating the liver-specific deletion of Uox in B-Uox flox, Alb cre mice .

Strain specific analysis of Uox gene expression in wild-type C57BL/6JNifdc mice and B-Uox flox, Alb cre mice by RT-qPCR. Liver and kidney RNA were isolated from wild-type C57BL/6JNifdc mice (+/+) (male, 6 week-old, n=3) and homozygous B-Uox flox, Alb cre mice (fl/fl) (male, 6 week-old, n=3). Values are expressed as mean ± SEM. ND: Not Detectable. Significance was determined by unpaired t-test. *P < 0.05, **P < 0.01, ***P < 0.001.

Western blot analysis of Uox protein expression in homozygous B-Uox flox, Alb cre mice. Heart, Liver, spleen, lung, kidney and brain were collected from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-Uox flox, Alb cre mice (fl/fl), and then analyzed by western blot with species-specific anti-Uox antibody (Santa cruz，sc-166214). 40 μg total proteins were loaded for western blotting analysis.

Serum uric acid analysis in wild-type C57BL/6 mice and homozygous B-Uox flox, Alb cre mice. Serum was collected from wild-type C57BL/6JNifdc mice (male and female, 9-week-old, n=6) and homozygous homozygous B-Uox flox, Alb cre mice (male and female, 9-week-old, n=10). Values are expressed as mean ± SEM. Significance was determined by unpaired t-test. *P < 0.05, **P < 0.01, ***P < 0.001.

Efficacy validation in B-Uox flox, Alb cre mice. Mice were divided into 4 groups (female and male, 12-weeks-old, n=4-6), B-Uox flox, Alb cre mice and B-Uox flox, Alb cre mice with 100 μg/ml allopurinol in drinking water. Values are expressed as mean ± SEM. Significance was determined by unpaired t-test. *P < 0.05, **P < 0.01, ***P < 0.001.