NCOA4-Mediated Ferroptosis Drives Tubulointerstitial Fibrosis in Hyperuricemia-Associated Chronic Kidney Disease

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.

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.

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 Fe²⁺ 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.

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.