Natural Polyphenols as Multi-Targeted Agents in Diabetic Foot Ulcer: A Comprehensive Systematic Review

Introduction: Diabetic foot ulcers (DFUs) are a debilitating complication of diabetes mellitus, with a prevalence of 4–10% and a high risk of infection and limb amputation. This review explores the therapeutic potential of polyphenols, plant-derived secondary metabolites, in promoting wound healing in DFUs. Methods: A systematic literature review was conducted in accordance with the PRISMA guidelines. Databases including PubMed, ISI Web of Knowledge, Google Scholar, and Scopus were searched for relevant studies from 1999 to 2025. Articles evaluating polyphenol-rich medicinal plants and their role in diabetic wound healing were selected based on defined inclusion and exclusion criteria. Results: Polyphenols such as curcumin, quercetin, gallic acid, resveratrol, and kaempferol demonstrated strong antioxidant, anti-inflammatory, and pro-angiogenic properties. These compounds modulate key molecular pathways—including VEGF, TGF-β, and NF-κB—resulting in enhanced fibroblast proliferation, collagen synthesis, and tissue regeneration. Plants like Curcuma longa, Punica granatum, and Vitis vinifera showed promising efficacy in both preclinical and limited clinical studies. Discussion: The evidence highlights the multi-targeted actions of polyphenols in addressing the impaired wound healing typical of diabetic conditions. However, limitations include variability in bioavailability, formulation inconsistencies, and a lack of standardized clinical trials. Conclusion: Polyphenols offer a promising, natural approach to managing DFUs, particularly in resource-limited settings. Their integration into therapeutic regimens may improve wound healing outcomes, though further clinical validation is necessary to optimize their use in mainstream diabetic care.