Targeted degradation of xanthine oxidase via PROTAC technology for the treatment of hyperuricaemia

Abstract

Hyperuricemia, characterized by an elevated serum uric acid level due to the abnormal xanthine oxidase (XOD)-mediated uric acid production, is generally associated with multiple systemic disorders. In this study, XOD-targeting proteolysis-targeting chimera (PROTAC) is developed to degrade the XOD and investigate the subsequent cellular behaviors. Febuxostat is a selective XOD inhibitor, designed to target XOD, and thalidomide functions as a ligand for the Cereblon (CRBN) E3 ubiquitin ligase. The two moieties are covalently linked via a polyethylene glycol (PEG) spacer. The synthesized chimera, DeXOD, combined with XOD, mediates the ubiquitination and degradation of target proteins in hepatocellular carcinoma cells (HepG2) via the proteasome pathway. In the hyperuricemia mouse, the DeXOD significantly reduces XOD and serum uric acid levels, and also alleviates the uric acid-induced inflammation and oxidative stress. The expression of renal inflammatory factors IL-1β, IL-18, and TNF-α is remarkably attenuated, accompanied by the elevation of superoxide dismutase (SOD) and glutathione (GSH) levels and the decrease of malondialdehyde (MDA). Furthermore, the DeXOD can ameliorate glomerular capsular dilatation and renal tubular epithelial damage, while demonstrating no observable hepatotoxic effects. This strategy effectively circumvents the therapeutic limitations of conventional xanthine oxidase inhibitors, thereby offering a promising therapeutic paradigm for hyperuricemia and its complications.