Hinokitiol modulates Nrf2/HO-1 signaling, autophagy, and URAT1 in hyperuricemia and oxidative stress models of renal injury.

Hyperuricemia (HUA), a metabolic disorder characterized by elevated serum uric acid levels, is a major risk factor for kidney injury and is closely associated with oxidative stress and autophagy dysregulation. This study investigates the renoprotective effects of hinokitiol, a natural tropolone derivative, in renal tubular epithelial cells and a potassium oxonate (PO)/hypoxanthine (HX)-induced hyperuricemia rat model. In vitro, hinokitiol significantly attenuated HO-induced cytotoxicity and reactive oxygen species (ROS) accumulation, which was associated with the activation of the Nrf2/HO-1 antioxidant pathway. Notably, hinokitiol restored autophagic flux by normalizing LC3B-II and p62 expression levels-an effect that was abolished by bafilomycin A1, indicating its dependence on intact lysosomal fusion. In vivo, hinokitiol improved renal function, reduced serum and urinary uric acid levels, and decreased malondialdehyde (MDA) concentrations, a marker of oxidative stress. Moreover, hinokitiol suppressed the overexpression of urate transporter 1 (URAT1) in hyperuricemic rats and enhanced uric acid excretion, as evidenced by increased fractional excretion of uric acid (FEUA) and creatinine clearance rate (CCr), without signs of hepatotoxicity. Collectively, these findings demonstrate that hinokitiol mitigates hyperuricemia-induced renal injury through coordinated regulation of oxidative stress, autophagy, and urate transport, highlighting its potential as a promising therapeutic agent for hyperuricemia-related kidney disease.