Work

Formononetin as a Natural Product-Derived Candidate for Diabetic Microvascular Complications: Mechanistic Evidence, Pharmacokinetics, Formulation Strategies, and Translational Barriers

Year: 2026

Type: review

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. Keywords: Astragalus membranaceus , SIRT1/PGC-1α, HIF-1α/VEGF, oxidative stress, angiogenesis, endothelial dysfunction

Source: Drug Design Development and Therapy

DOI: 10.2147/dddt.s623611