ABSTRACT Aim This study aimed to elucidate whether NCOA4‐mediated ferritinophagy promotes ferroptosis and contributes to renal tubulointerstitial fibrosis, and to clarify its interaction with the Nrf2 antioxidant pathway. Methods A uric acid (UA)‐induced ferroptosis model was established in HK‐2 cells and a hyperuricemic nephropathy (HN) model was constructed in C57BL/6 mice using adenine and potassium oxonate gavage. NCOA4 and Nrf2 were silenced by shRNA in vitro and AAV9‐mediated knockdown in vivo. Ferroptosis, oxidative stress and fibrosis were evaluated using qRT‐PCR, western blotting, immunofluorescence, biochemical assays and histopathological staining. Results UA exposure significantly increased NCOA4 expression, promoted ferritin degradation, and triggered iron accumulation, lipid peroxidation, and suppression of the Nrf2/GPX4/SLC7A11 axis. NCOA4 knockdown increased antioxidant defences, reduced Fe 2+ and ROS levels and alleviated α‐SMA and collagen IV expression in both HK‐2 cells and HN mice. However, co‐silencing Nrf2 abolished these protective effects, indicating functional coupling between NCOA4 and Nrf2 signalling. Conclusion NCOA4‐mediated ferritinophagy acts as an upstream driver of ferroptosis and tubulointerstitial fibrosis in hyperuricemia‐associated CKD. The NCOA4/Nrf2 axis represents a mechanistic link and potential therapeutic target for preventing renal fibrosis.
Wang et al. (Mon,) studied this question.