Inhibition of xanthine oxidase protects against heatstroke-related acute kidney injury

BACKGROUND: Heatstroke-induced acute kidney injury (HS-AKI) is a critical type of visceral injury. This study aimed to explore whether xanthine oxidase (XOD) promotes the progression of HS-AKI and whether febuxostat (Feb) attenuates HS-AKI through the inhibition of oxidative stress. MATERIALS AND METHODS: overexpression plasmid/siRNA) and pharmacologic intervention (febuxostat) were performed in HK-2 cells exposed to hyperthermia. In vivo, C57BL/6 mice were pretreated with febuxostat (or saline) before heat exposure, and the Control, Feb, HS, and Feb + HS groups were established. Quantitative proteomics was used to screen for proteins that were differentially expressed under thermal stress. Renal function, histopathology, oxidative stress (ROS, MDA, and SOD levels), expression levels f the cytoprotective protein HO-1, inflammatory cytokine (TNF-α and IL-1β), and apoptosis were thoroughly analyzed. RESULTS: Proteomic analysis revealed upregulated expression of XOD in the HS group compared with the control group. The activity and expression of the XOD enzyme were considerably higher in a high heat environment. XOD overexpression significantly increased HS-induced oxidative stress, the inflammatory response, and apoptosis in renal tubular epithelial cells. The inhibition of XOD with febuxostat markedly reduced oxidative stress, thereby preventing inflammation and apoptosis and alleviating HS-AKI. CONCLUSION: XOD-driven oxidative stress is a key pathogenic mechanism in HS-AKI. Febuxostat, a XOD inhibitor, showed protective efficacy in an animal model, highlighting this pathway as a potential therapeutic target.