Abstract
Diabetic foot ulcers (DFUs) constitute a significant global health burden; however, the influence of environmental heavy metals toxicity on their pathogenesis remains insufficiently investigated, particularly within low- and middle-income countries. This systematic review, conducted in strict accordance with PRISMA 2020 guidelines, assesses the impact of heavy metals exposure on the development, progression, and wound-healing kinetics of DFUs. A comprehensive search across PubMed/MEDLINE, Embase, Scopus, and Web of Science identified 32 eligible original studies. Quality appraisal was performed using the Newcastle-Ottawa Scale and SYRCLE’s Risk of Bias tool. Synthesized epidemiological and toxicological data consistently indicate that chronic exposure to non-essential heavy metals, specifically cadmium and lead, significantly augments DFU prevalence and clinical severity, demonstrating a 64% increase in DFU prevalence for each 1 µg/L increase in blood cadmium concentration. Mechanistically, these xenobiotics induce a ‘chronic inflammatory lock’ characterized by severe oxidative stress, sustained NLRP3 inflammasome activation, and the suppression of protective Metallothionein 2A (MT2A) pathways, thereby impeding microvascular angiogenesis. Conversely, deficiencies in essential trace elements, such as zinc and selenium, actively impair extracellular matrix maintenance. Advanced therapeutic interventions, including metal-ion-releasing hydrogels, cell-free exosome therapies, and systemic EDTA chelation, demonstrate significant potential to counteract heavy-metal-induced cellular suppression and facilitate tissue repair. This review underscores the imperative of integrating environmental toxicant screening and targeted detoxification strategies into standard multidisciplinary diabetic foot management.