Quercetin Attenuates Iron Overload-Induced Renal Injury via Activating Nrf2/xCT/GPX4 Signaling to Inhibit Ferroptosis

Iron overload, a key driver of ferroptosis, results from excessive iron accumulation in tissues and contributes to organ injury, including renal dysfunction. Increasing evidence indicates that ferroptosis plays an important role in the pathogenesis of kidney diseases. Natural antioxidants capable of regulating ferroptosis have therefore attracted growing attention. Quercetin (Que), a naturally occurring flavonoid, possesses well-documented antioxidant and anti-inflammatory properties and may provide protection against iron overload-induced renal injury. Present study aimed to clarify the molecular mechanisms underlying iron overload-induced nephrotoxicity and to evaluate the protective effects of Que through modulation of ferroptosis-related signaling pathways. Using in vivo and in vitro experimental approaches, we found that Que markedly reduced oxidative stress by regulating reactive oxygen species (ROS) levels, intracellular iron homeostasis, and the expression of ferroptosis-related proteins in renal tissues and HK-2 cells. The results demonstrate that iron overload induces renal injury primarily through activation of ferroptosis, characterized by iron-dependent lipid peroxidation and subsequent cellular damage. Importantly, Que significantly attenuated iron overload-induced renal injury by activating the NRF2/SLC7A11 (xCT)/GPX4 signaling pathway, thereby restoring antioxidant capacity and inhibiting ferroptotic cell death. In conclusion, Que protects against iron overload-induced renal injury by enhancing antioxidant defenses and maintaining iron homeostasis through inhibition of ferroptosis. These findings suggest that Que may represent a potential therapeutic strategy for kidney diseases associated with iron overload.