2. Academic Validation
  3. Dapagliflozin inhibits ferroptosis and ameliorates renal fibrosis in diabetic C57BL/6J mice

Dapagliflozin inhibits ferroptosis and ameliorates renal fibrosis in diabetic C57BL/6J mice

  • Sci Rep. 2025 Feb 28;15(1):7117. doi: 10.1038/s41598-025-91278-4.
Zhen Zhang # 1 2 3,  Luxin Li 4 5,  Yucen Dai # 2 6,  Yifei Lian # 3,  Haixu Song 7,  Xin Dai 3,  Ranyu Su 6,  Jiaxing Yin 7,  Ruimin Gu 8
Affiliations

Affiliations

  • 1 College of Pharmacy, Harbin Medical University, Harbin, 150000, Harbin, China.
  • 2 Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, 157000, Heilongjiang, China.
  • 3 School of First Clinical Medical College, Mudanjiang Medical University, Mudanjiang, 157000, China.
  • 4 Heilongjiang Key Laboratory of Tissue Damage and Repair, Mudanjiang Medical University, Mudanjiang, 157000, Heilongjiang, China. liluxin@mdjmu.edu.cn.
  • 5 College of Life Sciences, Mudanjiang Medical University, Mudanjiang, 157000, China. liluxin@mdjmu.edu.cn.
  • 6 College of Life Sciences, Mudanjiang Medical University, Mudanjiang, 157000, China.
  • 7 Affiliated Hongqi Hospital, Mudanjiang Medical University, Mudanjiang, 157000, China.
  • 8 College of Pharmacy, Harbin Medical University, Harbin, 150000, Harbin, China. ruimingu2916@163.com.
  • # Contributed equally.
PMID: 40016517 DOI: 10.1038/s41598-025-91278-4
Abstract

Diabetic nephropathy (DN) is a common complication of diabetes and a major cause of end-stage renal disease, with complex pathogenesis involving inflammation, oxidative stress, fibrosis, and Ferroptosis. Ferroptosis is linked to DN progression, yet treatment options are limited, particularly for targeting Ferroptosis. Dapagliflozin (DAPA), an SGLT2 Inhibitor, shows renal protective effects in diabetes, but its role in renal fibrosis and Ferroptosis in DN is unclear. This study investigated DAPA's effect on renal fibrosis in DN by inhibiting Ferroptosis, using a streptozotocin-induced diabetic mouse model. Results indicated that DAPA improved renal function, reduced fibrosis, and suppressed Ferroptosis markers in diabetic mice. In vitro, DAPA inhibited Ferroptosis and fibrosis in HK-2 cells under high glucose conditions. Molecular docking and network pharmacology suggested DAPA's anti-fibrotic and anti-ferroptotic effects may involve the Nrf2 and TGF-β signaling pathways. DAPA also reduced serum creatinine and blood urea nitrogen in diabetic mice, improved glomerulosclerosis and interstitial fibrosis, decreased iron deposition, and enhanced antioxidant activity. Overall, DAPA's multi-target mechanisms significantly improve DN progression, suggesting its potential as a targeted therapy against Ferroptosis. Future studies should further explore DAPA's applications.

Keywords

Dapagliflozin; Diabetic nephropathy; Ferroptosis; Renal fibrosis; TGF-β/Smad pathway.

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