Song SY, Shan CC, Zhou PP, Xu WL, Tan Y, Zhou XQ, Huang LJ, Yan QH, Yu JY. Nephroprotective mechanism of Kunkui Baoshen decoction in diabetic kidney disease: Targeting the HERC2/NCOA4-mediated autophagy-dependent ferroptosis pathway. World J Diabetes 2025; 16(10): 109568 [PMID: 41113495 DOI: 10.4239/wjd.v16.i10.109568]
Corresponding Author of This Article
Jiang-Yi Yu, MD, Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Qinhuai District, Nanjing 210000, Jiangsu Province, China. 1401743118@qq.com
Research Domain of This Article
Integrative & Complementary Medicine
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Si-Yuan Song, Chu-Chu Shan, Pei-Pei Zhou, Wei-Long Xu, Ying Tan, Xi-Qiao Zhou, Li-Ji Huang, Qian-Hua Yan, Jiang-Yi Yu, Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210000, Jiangsu Province, China
Co-first authors: Si-Yuan Song and Chu-Chu Shan.
Co-corresponding authors: Qian-Hua Yan and Jiang-Yi Yu.
Author contributions: Song SY and Shan CC designed the study and contributed equally to this work as co-first authors; Zhou PP, Xu WL, and Tan Y carried out the experiments; Huang LJ, Zhou XQ, Yan QH, and Yu JY provided experiment assistance; Yu JY and Yan QH contributed equally to this work as co-corresponding authors. All authors have read and approved the final manuscript.
Supported by National Natural Science Foundation of China, No. 82205025, No. 82374355, and No. 82174293.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Affiliated Hospital of Nanjing University of Chinese Medicine, No. 2023DW-039-02.
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: The raw data are available upon reasonable request from the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jiang-Yi Yu, MD, Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, No. 155 Hanzhong Road, Qinhuai District, Nanjing 210000, Jiangsu Province, China. 1401743118@qq.com
Received: May 15, 2025 Revised: June 3, 2025 Accepted: August 15, 2025 Published online: October 15, 2025 Processing time: 153 Days and 20 Hours
Abstract
BACKGROUND
Diabetic kidney disease (DKD) stands as the key contributor to chronic kidney disease worldwide. Clinical studies have shown that Kunkui Baoshen decoction (KKBS) effectively reduces proteinuria and enhances renal function in DKD patients. However, its precise molecular targets and therapeutic mechanisms remain to be thoroughly clarified.
AIM
To evaluate the nephroprotective efficacy of KKBS in DKD and explore the underlying mechanisms of action.
METHODS
Liquid chromatography-tandem mass spectrometry was utilized to analyze the chemical constituents of KKBS. Metabonomic and transcriptomic analyses were conducted to identify key targets and pathways associated with the therapeutic effects of KKBS on DKD. The nephroprotective effects of KKBS were assessed both in high glucose-induced human kidney-2 cells and in db/db mice. A variety of assays were performed, including Cell Counting Kit-8, Western blot, quantitative reverse transcription-polymerase chain reaction, immunofluorescence, co-immunoprecipitation, periodic acid-Schiff staining, Masson staining, hematoxylin and eosin staining, immunohistochemistry, and mitochondrial morphology analysis.
RESULTS
The glutathione metabolic pathway emerged as the most prominent metabolic pathway in the metabonomic analysis of KKBS. Transcriptomic and bioinformatic analyses revealed that nuclear receptor coactivator 4 (NCOA4) was instrumental in regulating ferroptosis within renal tubules of mice with DKD. Both in vitro and in vivo experiments showed that KKBS ameliorated renal dysfunction, mitigated renal tissue damage, and repressed the expression of autophagy-dependent ferroptosis markers and inflammatory fibrosis. Mechanistically, KKBS enhanced the interaction between the homologous to E6-AP C-terminus and RCC1-like domain-containing E3 ubiquitin protein ligase (HERC2) and NCOA4, leading to K48-related ubiquitination and subsequent degradation of NCOA4. This process inhibited autophagy-dependent ferroptosis, reduced the release of pro-fibrotic inflammatory factors, and ultimately exerted an anti-fibrotic effect in DKD.
CONCLUSION
KKBS confers nephroprotection in DKD by modulating HERC2/NCOA4-mediated autophagy-dependent ferroptosis, thereby alleviating renal fibrosis.
Core Tip: Kunkui Baoshen decoction (KKBS), a traditional Chinese herbal formula, exerts renoprotective effects in diabetic kidney disease (DKD) by inhibiting autophagy-dependent ferroptosis. Through integrated transcriptomic and metabolomic analyses, we identified the homologous to E6-AP C-terminus and RCC1-like domain-containing E3 ubiquitin protein ligase/nuclear receptor coactivator 4 axis as a critical therapeutic target. KKBS enhances homologous to E6-AP C-terminus and RCC1-like domain-containing E3 ubiquitin protein ligase-mediated K48-linked ubiquitination of nuclear receptor coactivator 4, promoting its degradation and thereby suppressing ferroptosis, renal inflammation, and fibrosis in high glucose-induced human kidney-2 cells and db/db mice. This research reveals a novel pathway through which KKBS regulates ferroptosis to prevent DKD progression.
