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©The Author(s) 2026. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Feb 15, 2026; 17(2): 112500
Published online Feb 15, 2026. doi: 10.4239/wjd.v17.i2.112500
Published online Feb 15, 2026. doi: 10.4239/wjd.v17.i2.112500
Formononetin inhibits p53 signaling pathway activation to delay cellular senescence and ameliorates diabetic kidney disease
Yue Ji, Pei-Yue He, Yi-Min Zhou, Bo Nie, Yu-Ning Liu, Wei-Jing Liu, Institute of Nephrology & Beijing Key Laboratory, Dongzhimen Hospital, Beijing University of Traditional Chinese Medicine, Beijing 100010, China
Rui-Xin Liu, Beijing Bei Zhong Asset Management Co. Ltd, Beijing University of Chinese Medicine, Beijing 100029, China
Ya-Chun Li, Department of Nephrology, Shaanxi Provincial Hospital of Chinese Medicine, Xi’an 710003, Shanxi Province, China
Jing Guo, Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical, Beijing 100700, China
Co-first authors: Yue Ji and Rui-Xin Liu.
Co-corresponding authors: Yu-Ning Liu and Wei-Jing Liu.
Author contributions: Ji Y and Liu RX assisted with experimental execution, data collection, and statistical analysis as co-first authors; Liu YN and Liu WJ contribute equally to this study as co-corresponding authors; Ji Y, Liu RX and He PY contributed equally to this work. They designed and performed the experiments, analyzed the data, and drafted the manuscript; Zhou YM, Li YC and Guo J contributed to the animal model establishment and in vivo experiments; Nie B, Liu YN, and Liu WJ supervised the project, provided critical intellectual input, interpreted results, and revised the manuscript; all authors reviewed and approved the final version of the manuscript.
Supported by National Natural Science Foundation of China Youth Program, No. 82405313, No. 82204821 and No. 82205037; National Natural Science Foundation of China, No. 82274293; Dongzhimen Hospital Grant, No. DZMG-XZYY-23002, No. DZMG-ZJXY-23004 and No. DZMG-QNZX-24005; the China Postdoctoral Science Foundation, No. 2024M760287; and National Major Science and Technology Project, No. 2025ZD0549600.
Institutional animal care and use committee statement: In all animal experiments, the animals were treated ethically and humanely, and the experiments were approved by the Institutional Animal Care and Use Committee of Dongzhimen Hospital (Approval No. DZMYY-24-07).
Conflict-of-interest statement: There is no conflict of interest associated with any of the senior author or other coauthors contributed their efforts in this manuscript.
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: All primary research outputs are embedded in the text, while raw records can be procured from the designated author via formal inquiry. Data available on request.
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: Wei-Jing Liu, Academic Fellow, Professor, Institute of Nephrology & Beijing Key Laboratory, Dongzhimen Hospital, Beijing University of Traditional Chinese Medicine, No. 5 Haiyuncang, Dongcheng District, Beijing 100010, China.
Received: July 30, 2025
Revised: October 16, 2025
Accepted: December 18, 2025
Published online: February 15, 2026
Processing time: 192 Days and 2.9 Hours
Revised: October 16, 2025
Accepted: December 18, 2025
Published online: February 15, 2026
Processing time: 192 Days and 2.9 Hours
Core Tip
Core Tip: Transcriptomic profiling identified the p53 signaling pathway as the key mechanism through which formononetin (FN) alleviates diabetic kidney disease (DKD). FN upregulates MDM2 expression, thereby inhibiting p53 transcriptional activity—as confirmed by dual-luciferase reporter assay—and downregulating p21, leading to reduced senescence markers (β-galactosidase and senescence-associated secretory phenotype factors) in both podocytes and DKD mice. Notably, MDM2 gene silencing abrogates the anti-senescent effects of FN, establishing MDM2 as essential to its action. Overall, FN improves renal function and pathology by targeting the p53/MDM2/p21 axis to attenuate cellular senescence.