Exploring the Role of Febuxostat's Drug Target XOR in Erectile Dysfunction: Insights from Human Genetics and Rat Models

Zhibin Chen¹Yuqi Li²Chunyang Meng²Xiaorong Li¹Huan Liao¹Xiong Li²Yang Zeng²Xu Li²Tao Zhou³Qingfu Deng^2*

• ¹The First People's Hospital of Neijiang, Neijiang, China
• ²The Affiliated Hospital of Southwest Medical University, Luzhou, China
• ³North Sichuan Medical College, Nanchong, China

Background: The use of the uric acid-lowering drug Febuxostat (FB) has been associated with the risk of erectile dysfunction (ED) in men; however, findings from previous studies remain inconsistent. This study aimed to investigate the association between FB target genes and ED, as well as the underlying mechanisms involved. Methods: FB target genes were obtained from the DrugBank database. Mendelian randomization (MR) analysis was employed to determine the causal relationship between the target gene xanthine oxidoreductase (XOR) and ED. Molecular docking was then performed to assess the binding affinity between FB and XOR. A hyperuricemic rat model with ED was established, and several parameters were evaluated, including ICPmax/MAP ratio, serum testosterone, XOR, and p-eNOS/eNOS expression levels. In addition, levels of nitric oxide (NO), superoxide dismutase (SOD), malondialdehyde (MDA), and apoptosis in corpus cavernosum tissue were measured. Results: MR analysis revealed that XOR was significantly associated with an increased risk of ED (95% CI: 2.724–27.232; P < 0.001). Molecular docking confirmed a stable binding interaction between FB and XOR (binding energy: –8.2 kcal/mol). After one month of continuous oral administration of FB, XOR and MDA levels and the apoptosis rate in the corpus cavernosum were significantly reduced in hyperuricemic ED rats, while p-eNOS expression, the p-eNOS/eNOS ratio, and levels of NO and SOD were markedly increased. Conclusion: FB reducing oxidative stress and apoptosis in penile corpus cavernosum tissue in hyperuricemic rats by inhibiting XOR, thereby ameliorates ED.