Phytotherapeutic Regulation of Matrix Metalloproteinases in Diabetic Foot Ulcer: Molecular Mechanisms and Wound Healing Perspectives

ABSTRACT Diabetic foot ulcer (DFU) constitutes one of the most clinically significant and economically burdensome complications of diabetes mellitus, conferring substantial morbidity, progressive deterioration of patient quality of life, and an elevated risk of nontraumatic lower‐limb amputation. Epidemiological studies indicate that approximately 34% of individuals with type II diabetes will develop a foot ulcer during their lifetime, with peripheral neuropathy, vascular insufficiency, suboptimal glycemic control (HbA1c), subdermal trauma, obesity, and age identified as principal predisposing factors. The pathophysiology of DFU is distinguished by an extensive dysregulation of the wound healing pathways, wherein the sequential phases of hemostasis, inflammation, proliferation, and tissue remodeling are collectively impaired. Of particular mechanistic relevance, the aberrant overactivation of matrix metalloproteinases (MMPs) and their imbalance with tissue inhibitors of metalloproteinases (TIMPs) lead to unrestrained degradation of the extracellular matrix (ECM) and inhibits tissue regeneration. This proteolytic imbalance is further aggravated by the dysregulation of nuclear factor kappa B (NF‐κβ), transforming growth factor‐β (TGF‐β), vascular endothelial growth factor (VEGF), and fibroblast growth factor (FGF) signaling pathways, collectively perpetuating a pro‐inflammatory, anti‐angiogenic wound microenvironment. Contemporary clinical management strategies focus on (a) dressing, (b) anti‐diabetic drugs such as metformin, insulin, sulfonylureas, dipeptidyl peptidase‐4 (DPP‐4) inhibitors, and thiazolidinediones, (c) growth factors that enhance the healing process, (d) stem cells, and (e) scaffolds; however, their therapeutic efficacy remains insufficient for a substantial proportion of patients. This review critically appraises the molecular dysregulations involved in DFU and the influence of bioactive compounds on wound‐healing pathways.