Mechanistic Insights into the Wound Healing Activity of Plant Species in Diabetic Ulcers

Diabetic foot ulcers represent a major complication driven by chronic inflammation, oxidative stress, impaired angiogenesis, and defective extracellular matrix remodeling. This integrative review synthesizes mechanistic evidence from 51 preclinical studies evaluating plant-derived interventions in diabetic animal models. Database searches (PubMed, Embase, Scopus) identified species modulating discrete molecular targets across healing phases. In the inflammatory phase, extracts suppressed NF-κB-dependent cytokine production (IL-1β, TNF-α, IL-6), reduced oxidative stress via Nrf2/HO-1 activation, and disrupted AGE-RAGE signaling, facilitating neutrophil resolution and macrophage reprogramming. During proliferation, interventions upregulated angiogenic factors (VEGF, bFGF, IGF-1) through ERK1/2 and PI3K/Akt-eNOS pathways, stimulated fibroblast proliferation, and enhanced collagen deposition. In the remodeling phase, extracts improved tensile strength by modulating MMP-2/9 and TIMP-2 balance, promoting type I collagen maturation and organized fiber architecture. Polyphenol-rich species (<i>Punica granatum</i>, <i>Quercus infectoria</i>, <i>Polygonatum kingianum</i>) demonstrated the most robust multi-target activity. However, translational gaps persist due to extract heterogeneity, limited phytochemical standardization, and overreliance on young male rodent models. Future development requires standardized bioactive quantification, dose-response characterization, advanced delivery systems (hydrogels, nanofibers), and validation in aged animals with comorbidities. These mechanistic insights support plant-based therapies as multi-component adjuvants targeting the complex pathophysiology of diabetic ulcers.