Xanthohumol attenuates renal ischemia/reperfusion injury by inhibiting ferroptosis

Ischemia/reperfusion injury (IRI) is a notable contributor to kidney injury, but effective prevention and treatment options are limited. The present study aimed to evaluate the impact of xanthohumol (XN), a kind of flavonoid, on renal IRI and its pathological process in rats. Rats and HK-2 cells were divided into five groups: Sham (control), IR [hypoxia-reoxygenation (HR)], IR (HR) + XN, IR (HR) + erastin or IR (HR) + XN + erastin. The effects of XN and erastin (a ferroptosis inducer) on IRI in rats were evaluated using blood urea nitrogen, plasma creatinine, glutathione, superoxide dismutase and malondialdehyde kits, western blotting, cell viability assay, hematoxylin and eosin staining and reactive oxygen species (ROS) detection. Nrf2 small interfering (si)RNA was used to investigate the role of the Nrf2/heme oxygenase (HO)-1 axis in XN-mediated protection against HR injury. Cell viability, ROS levels and expression of ferroptosis-related proteins were analyzed. Following IR, renal function of rats was severely impaired and oxidative stress and ferroptosis levels significantly increased. However, XN treatment decreased renal injury and inhibited oxidative stress and ferroptosis in renal tubular epithelial cells. Additionally, XN upregulated the Nrf2/HO-1 signaling pathway and Nrf2-siRNA reversed the renoprotective effect of XN. XN effectively decreased renal IRI by inhibiting ferroptosis and oxidative stress and its protective mechanism may be associated with the Nrf2/HO-1 signaling pathway.