Nrf2 attenuates diquat-induced renal ferroptosis by regulating mitochondrial ferritin

This study investigated ‌the protective effect of nuclear factor erythroid 2-related factor 2 (Nrf2) against diquat-induced acute kidney injury (AKI) by regulating mitochondrial ferritin (FtMt). A model of kidney injury was established in male Wistar rats by oral gavage of diquat. The rats were randomly assigned to four experimental groups: control, diquat, diquat + Liproxstatin-1 (Lip-1, a ferroptosis inhibitor), and diquat + Sulforaphane (SFN, an Nrf2 activator). Kidney injury markers, oxidative stress levels, and the expression of ferroptosis-related proteins, Nrf2 and FtMt, were assessed. Results showed that Diquat induced dose- and time-dependent AKI and ferroptosis, with a significant decrease in the expressions of Glutathione Peroxidase 4 (GPX4), cystine/glutamate antiporter solute carrier family 7 member 11 (SLC7A11; also known as xCT), and Nrf2. Concurrently, diquat also upregulated the expression of ferritin heavy chain 1 (FTH1) and FtMt. Inhibition of ferroptosis alleviated AKI while upregulating Nrf2 and downregulating FtMt expression. SFN targeted the activation of Nrf2 expression, which significantly alleviated ferroptosis and downregulated the FtMt expression. Immunofluorescence co-localization analysis further revealed co-localization of Nrf2 and FtMt in kidney tissues. In conclusion, these findings demonstrate that Nrf2 activation attenuates diquat-induced renal ferroptosis by modulating FtMt expression, suggesting that they may serve as a potential therapeutic target for preventing diquat-induced kidney injury.