Liu C, Li Y, Zhang Y, Gao M, Yang SF. Hyperoside attenuates diabetic nephropathy by activating the Nrf2/SLC7A11/GPX4 axis to restrain ferroptosis. World J Diabetes 2026; 17(4): 114679 [DOI: 10.4239/wjd.v17.i4.114679]
Corresponding Author of This Article
Shi-Feng Yang, MD, Department of Nephrology, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an 710061, Shaanxi Province, China. jeffysy@126.com
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Urology & Nephrology
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Basic Study
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Apr 15, 2026 (publication date) through Apr 14, 2026
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World Journal of Diabetes
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1948-9358
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Liu C, Li Y, Zhang Y, Gao M, Yang SF. Hyperoside attenuates diabetic nephropathy by activating the Nrf2/SLC7A11/GPX4 axis to restrain ferroptosis. World J Diabetes 2026; 17(4): 114679 [DOI: 10.4239/wjd.v17.i4.114679]
World J Diabetes. Apr 15, 2026; 17(4): 114679 Published online Apr 15, 2026. doi: 10.4239/wjd.v17.i4.114679
Hyperoside attenuates diabetic nephropathy by activating the Nrf2/SLC7A11/GPX4 axis to restrain ferroptosis
Chao Liu, Yan Li, Yuan Zhang, Ming Gao, Shi-Feng Yang
Chao Liu, Yan Li, Shi-Feng Yang, Department of Nephrology, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
Yuan Zhang, Ming Gao, Department of Nephrology, Xi’an People’s Hospital (Xi’an Fourth Hospital), Xi’an 710004, Shaanxi Province, China
Author contributions: Liu C and Li Y performed the research; Liu C, Zhang Y, and Gao M collected and analyzed the data; Liu C and Yang SF drafted the manuscript; Yang SF designed the research; and all authors critically reviewed and approved the final version of the article.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Health Science Center of Xi’an Jiaotong University, approval No. XJTUAE2025-3549.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Corresponding author: Shi-Feng Yang, MD, Department of Nephrology, The First Affiliated Hospital of Xi’an Jiaotong University, No. 277 Yanta West Road, Xi’an 710061, Shaanxi Province, China. jeffysy@126.com
Received: September 26, 2025 Revised: November 1, 2025 Accepted: February 5, 2026 Published online: April 15, 2026 Processing time: 200 Days and 18.2 Hours
Abstract
BACKGROUND
Diabetic nephropathy (DN) is a major cause of end-stage renal disease. Despite their ability to delay the progression of DN, current therapies do not halt renal injury. Ferroptosis, a regulated form of cell death characterized by iron-dependent lipid peroxidation, contributes to DN pathogenesis.
AIM
To test the hypothesis that hyperoside—a natural flavonoid—protects against DN by activating the Nrf2/SLC7A11/GPX4 antioxidant signaling pathway, thereby reducing ferroptosis and oxidative stress-related renal injury.
METHODS
High-glucose-treated HK-2 cells and streptozotocin-induced DN rats were used to evaluate the effects of hyperoside. Cell viability, apoptosis, oxidative stress, and ferroptosis markers were measured using Cell Counting Kit-8, terminal deoxynucleotidyl transferase dUTP nick-end labeling, flow cytometry, enzyme-linked immunosorbent assay, quantitative reverse transcription polymerase chain reaction, and Western blotting. Mechanistic validation was performed using erastin, ferrostatin-1, and Nrf2 small interfering RNAs.
RESULTS
Hyperoside significantly improved HK-2 cell viability under high-glucose conditions and reduced apoptosis, with 50 μmol/L showing the most consistent protection. It decreased lactate dehydrogenase, malondialdehyde, Fe2+, and lipid reactive oxygen species levels and restored glutathione as well as Nrf2, SLC7A11, and GPX4 expression, effects comparable to the ferroptosis inhibitor ferrostatin-1 (all P < 0.05). In streptozotocin-induced DN rats, hyperoside (50 mg/kg) lowered serum creatinine, blood urea nitrogen, and urinary albumin excretion, ameliorated glomerular and tubular lesions, and upregulated renal Nrf2/SLC7A11/GPX4 expression (all P < 0.05).
CONCLUSION
Hyperoside alleviates diabetic renal injury by activating the Nrf2/SLC7A11/GPX4 pathway and suppressing ferroptosis-driven oxidative damage. These findings provide mechanistic and experimental evidence supporting hyperoside as a potential therapeutic candidate for DN.
Core Tip: This study, for the first time, demonstrates that hyperoside, a natural flavonoid, protects against diabetic nephropathy by suppressing ferroptosis via activation of the Nrf2/SLC7A11/GPX4 antioxidant axis. In high-glucose-challenged HK-2 cells, hyperoside restored glutathione, reduced lipid reactive oxygen species and Fe2+ accumulation, and improved cell viability, effects comparable to ferrostatin-1. In streptozotocin-induced diabetic nephropathy rats, hyperoside ameliorated renal dysfunction and histologic injury while upregulating Nrf2/SLC7A11/GPX4. These findings provide mechanistic and experimental support for hyperoside as a potential therapeutic candidate for diabetic nephropathy.
