Bardoxolone methyl inhibits ferroptosis through the Keap1‑Nrf2 pathway in renal tubular epithelial cells.

Abstract

Diabetic kidney disease (DKD), a primary cause of end‑stage kidney disease, involves ferroptosis in renal tubular epithelial cells (RTECs). Bardoxolone methyl (BM), known for its antioxidant and anti‑inflammatory properties, activates the Keap1‑Nrf2 pathway and has slows kidney function decline. 2‑Deoxy‑d‑ribose (dRib) can induce ferroptosis in RTECs by promoting the degradation of solute carrier family 7 member 11 (SLC7A11), a protein essential for cystine transport and glutathione (GSH) synthesis. The present study aimed to evaluate whether BM could inhibit dRib‑induced ferroptosis in RTECs and to elucidate the underlying mechanisms. Using NRK‑52E cells and primary RTECs, cystine uptake, GSH and iron levels, cell viability, lipid peroxidation and ferroptosis‑related markers were assessed. Co‑immunoprecipitation was used to assess Keap1‑Nrf2 interactions and confocal microscopy was employed to observe Nrf2 nuclear translocation. BM pretreatment dose‑dependently restored cystine uptake, increased GSH levels and improved cell viability, while reducing intracellular iron accumulation and lipid peroxidation triggered by dRib. These protective effects were attenuated by Nrf2 inhibitors, indicating that the activity of BM is Nrf2‑dependent. BM enhanced Nrf2 protein expression, upregulated SLC7A11 and increased the expression of Nrf2‑ARE target genes, including heme oxygenase‑1, NADPH quinone oxidoreductase 1, glutamate‑cysteine ligase catalytic subunit and glutamate‑cysteine ligase modifier subunit, while suppressing ferroptosis‑related markers (acyl‑CoA synthetase long chain family member 4, ChaC glutathione‑specific gamma‑glutamylcyclotransferase 1 and prostaglandin‑endoperoxide synthase 2). Furthermore, BM disrupted the Nrf2‑Keap1 interaction, promoting Nrf2 nuclear translocation. In conclusion, BM may disrupt the Keap1‑Nrf2 interaction in RTECs, upregulate SLC7A11 and mitigate dRib‑induced ferroptosis, thereby presenting a potential therapeutic option to prevent the progression of DKD by protecting RTECs from ferroptosis.