Dapagliflozin attenuates ferroptosis in diabetic nephropathy through activation of the Nrf2/HO‑1 signaling pathway.

Abstract

Renal tubular injury has emerged as a critical determinant in the pathogenesis of diabetic nephropathy (DN). Ferroptosis, a recently characterized mode of iron‑dependent regulated cell death, has been implicated in the development of renal tubular damage. Dapagliflozin (DAPA), a sodium‑glucose cotransporter 2 inhibitor, has demonstrated efficacy in attenuating DN progression and preserving renal function. The present study sought to elucidate the inhibitory mechanisms by which DAPA modulates ferroptosis in DN. To this aim, the expression profiles of key molecular markers within the ferroptosis cascade were systematically evaluated using 6‑week‑old male C57BL/6J mice and high‑glucose‑cultured human renal tubular epithelial cells as experimental models. The findings revealed that DAPA notably ameliorated renal histopathological alterations, upregulated the expression of solute carrier family 7 member 11, glutathione peroxidase 4 and ferritin heavy chain 1, whilst concomitantly downregulating transferrin receptor 1. These effects were mediated through the activation of nuclear factor erythroid 2‑related factor 2 (Nrf2) and heme oxygenase‑1 (HO‑1) in C57BL/6J mice. Collectively, these data indicate that the reno‑protective effects of DAPA in DN may be attributable to the suppression of ferroptosis via activation of the Nrf2/HO‑1 signaling axis.

Key Findings

• Dapagliflozin ameliorates renal histopathological alterations in diabetic nephropathy.
• Dapagliflozin upregulates solute carrier family 7 member 11, glutathione peroxidase 4, and ferritin heavy chain 1 while downregulating transferrin receptor 1.
• The effects of dapagliflozin are mediated through activation of the Nrf2/HO-1 signaling pathway, leading to suppression of ferroptosis.

Clinical Significance

Citation

Liu Hanshuang, Zhang Xiaoxiao, Cui Yubinget al.. Dapagliflozin attenuates ferroptosis in diabetic nephropathy through activation of the Nrf2/HO‑1 signaling pathway. International journal of molecular medicine. 2026-Jul.