Introduction and Objective: Ferroptosis of renal tubular epithelial cells (RTECs) is implicated in the pathogenesis of diabetic kidney disease (DKD). Bardoxolone methyl (BM), a synthetic triterpenoid with antioxidant and anti-inflammatory properties, has shown promise in clinical trials for preventing DKD-related renal decline but carries a risk of heart failure. Recent studies revealed that 2-deoxy-D-ribose (dRib) induces ferroptosis in RTECs by degrading system χc- (SLC7A11). This study investigates whether BM inhibits dRib-induced ferroptosis and elucidates the mechanisms involved.Methods: Using NRK-52E cells and primary RTECs, the researchers assessed cystine uptake, GSH and iron levels, cell viability, lipid peroxidation, and ferroptosis-related markers. Nrf2 and Keap1 interactions were evaluated using co-immunoprecipitation, and Nrf2 nuclear translocation was observed via confocal microscopy.Results: BM pretreatment dose-dependently restored cystine uptake, GSH levels, and cell viability while reducing intracellular iron and lipid peroxidation caused by dRib. The effects were diminished by Nrf2 inhibitors, indicating BM’s dependence on Nrf2 activation. BM enhanced Nrf2 protein expression, upregulated SLC7A11, and increased expression of Nrf2-ARE target genes (HO1, NQO1, GCLC), while suppressing ferroptosis-related markers (ACSL4, CHAC1, PTGS2). BM disrupted the Nrf2-Keap1 interaction, promoting Nrf2 nuclear translocation.Conclusion: BM inhibits dRib-induced ferroptosis in RTECs by disrupting the association between Nrf2 and Keap1, thereby enhancing Nrf2 nuclear translocation and increasing SLC7A11 gene expression. These findings highlight the therapeutic potential of targeting the Keap1-Nrf2/SLC7A11 axis for DKD treatment without heart failure risk.
J. Han: None. J. Bae: None. S. Yoo: None. S. Lee: None. G. Koh: None.
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