Amelioration of UUO-Induced Renal Fibrosis by "Yu Fang" via Suppression of Ferroptosis-Mediated Tubular Injury and Inflammation

AimTo investigate the role of ferroptosis in renal fibrosis induced by unilateral ureteral obstruction (UUO) and to elucidate the antifibrotic mechanism of the traditional Chinese medicine formula Yu Fang through the GPX4 axis.MethodsA UUO rat model was established and divided into four groups: sham-operated, UUO, UUO + Yu Fang, and UUO + ferrostatin-1 (Fer-1). Renal morphology, function, and fibrosis were evaluated using histopathology and biochemical assays. Ferroptosis-related indicators, including GPX4 expression, lipid peroxidation, and glutathione (GSH) levels, were assessed using immuno-histochemistry, Western blot, and ELISA.ResultsThe UUO group exhibited marked tubular injury, renal dysfunction, and collagen deposition. Renal tissues showed characteristic features of ferroptosis, such as decreased GPX4 expression, elevated lipid peroxidation, and excessive hydroxyproline accumulation. Both Yu Fang and Fer-1 treatment significantly alleviated tubular damage, restored renal function, and reduced collagen deposition. Mechanistically, Yu Fang enhanced the GSH-GPX4 antioxidant axis, reduced lipid peroxidation, and inhibited ferroptosis. Furthermore, Yu Fang suppressed the expression of profibrotic factors and inhibited myofibroblast activation, thereby attenuating renal interstitial fibrosis.ConclusionsFerroptosis plays a critical role in UUO-induced renal fibrosis. Yu Fang mitigates ferroptosis and fibrosis progression by modulating the GSH-GPX4 axis, reducing oxidative stress and myofibroblast activation. These findings provide experimental evidence supporting Yu Fang as a promising therapeutic strategy for renal fibrosis targeting ferroptosis.