Formononetin as a Natural Product-Derived Candidate for Diabetic Microvascular Complications: Mechanistic Evidence, Pharmacokinetics, Formulation Strategies, and Translational Barriers
- 1The College of Traditional Chinese Medicine, Guangdong Pharmaceutical University, Guangzhou, 510006, People’s Republic of China
- 2Senior Department of Nephrology, Chinese PLA General Hospital, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing, 100853, People’s Republic of China
- 3School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China
Abstract
Diabetic microvascular complications (DMCs) mainly affect the kidneys, retina, and peripheral nerves. Their treatment remains challenging because these complications involve overlapping metabolic, inflammatory, vascular, and neurodegenerative changes. Formononetin, an isoflavone derived from Astragalus membranaceus, has shown protective effects in several preclinical models of microvascular injury. This review summarizes the current evidence on formononetin in DMCs, with attention to proposed mechanisms, pharmacokinetic features, formulation strategies, and barriers to clinical translation. In diabetic kidney disease models, preclinical studies suggest that formononetin may reduce oxidative stress through pathways related to SIRT1/PGC-1α and Nrf2. It may also lessen mitochondrial dysfunction, inflammation, and fibrotic remodeling. In retinal hypoxia and oxygen-induced retinopathy models, formononetin has been reported to modulate HIF-1α/VEGF-related angiogenic responses. However, whether these findings apply directly to diabetic retinopathy, especially proliferative diabetic retinopathy, still needs to be examined in diabetes-specific models. Evidence for diabetic neuropathy, diabetic cardiomyopathy, and diabetic wound healing is more limited and is mainly based on preclinical findings or indirect mechanistic evidence. Overall, formononetin should be considered a preclinical candidate for DMC-related research rather than a clinically established intervention. Further translation will require human PK/PD studies, standardized formulations, rational dose-conversion analysis, GLP-compliant toxicology, reproductive and endocrine safety evaluation, and assessment of CYP-mediated drug interactions.
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BibTeX
@article{gao2026formononetin,
title = {{Formononetin as a Natural Product-Derived Candidate for Diabetic Microvascular Complications: Mechanistic Evidence, Pharmacokinetics, Formulation Strategies, and Translational Barriers}},
author = {Xiaotian Gao and Yingtao Zhang and Yan Zheng and Luying Qiao and Xiaoling Liu and Sifan Yang and Xun Chen and Yunming Xiao and Xu Wang and Ran Liu and Zheyi Dong and Qian Wang and Xiangmei Chen and Quan Hong},
journal = {Drug Design, Development and Therapy},
year = {2026},
month = oct,
doi = {10.2147/dddt.s623611},
url = {https://doi.org/10.2147/dddt.s623611},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Formononetin as a Natural Product-Derived Candidate for Diabetic Microvascular Complications: Mechanistic Evidence, Pharmacokinetics, Formulation Strategies, and Translational Barriers
AU - Xiaotian Gao
AU - Yingtao Zhang
AU - Yan Zheng
AU - Luying Qiao
AU - Xiaoling Liu
AU - Sifan Yang
AU - Xun Chen
AU - Yunming Xiao
AU - Xu Wang
AU - Ran Liu
AU - Zheyi Dong
AU - Qian Wang
AU - Xiangmei Chen
AU - Quan Hong
PY - 2026
DA - 2026/10/28
JO - Drug Design, Development and Therapy
DO - 10.2147/dddt.s623611
UR - https://doi.org/10.2147/dddt.s623611
AB - Diabetic microvascular complications (DMCs) mainly affect the kidneys, retina, and peripheral nerves. Their treatment remains challenging because these complications involve overlapping metabolic, inflammatory, vascular, and neurodegenerative changes. Formononetin, an isoflavone derived from Astragalus membranaceus, has shown protective effects in several preclinical models of microvascular injury. This review summarizes the current evidence on formononetin in DMCs, with attention to proposed mechanisms, pharmacokinetic features, formulation strategies, and barriers to clinical translation. In diabetic kidney disease models, preclinical studies suggest that formononetin may reduce oxidative stress through pathways related to SIRT1/PGC-1α and Nrf2. It may also lessen mitochondrial dysfunction, inflammation, and fibrotic remodeling. In retinal hypoxia and oxygen-induced retinopathy models, formononetin has been reported to modulate HIF-1α/VEGF-related angiogenic responses. However, whether these findings apply directly to diabetic retinopathy, especially proliferative diabetic retinopathy, still needs to be examined in diabetes-specific models. Evidence for diabetic neuropathy, diabetic cardiomyopathy, and diabetic wound healing is more limited and is mainly based on preclinical findings or indirect mechanistic evidence. Overall, formononetin should be considered a preclinical candidate for DMC-related research rather than a clinically established intervention. Further translation will require human PK/PD studies, standardized formulations, rational dose-conversion analysis, GLP-compliant toxicology, reproductive and endocrine safety evaluation, and assessment of CYP-mediated drug interactions.
SN - 1177-8881
ER -