Time to Heal: MicroRNA Temporal Dysregulation in Diabetic Foot Ulcers

Diabetic foot ulcers (DFUs) are a severe complication of diabetes characterized by delayed healing, infection susceptibility, and tissue necrosis. During normal healing, microRNA (miRNA) expression changes over time and helps regulate inflammation, tissue formation, and matrix remodeling. The same miRNA can serve opposing roles depending on cell type, timing, and wound context. Hyperglycemia, hypoxia, and oxidative stress disrupt these processes and prolong inflammation. This review examines how altered miRNA regulation may impair wound-healing transitions and vessel maturation in DFUs. We organize findings from experimental models and human samples into three interpretive patterns: delayed or insufficient induction, aberrant persistence, and temporal inversion or phase-inappropriate expression. Angiogenesis provides an example of how disrupted miRNA timing may impair vascular repair and granulation tissue formation. Circadian regulation may further influence these processes, although direct evidence linking circadian regulation, miRNA dynamics, and human DFUs remains limited. Preclinical studies of miRNA combinations, engineered vesicles, and biomaterial carriers suggest opportunities to coordinate local miRNA delivery with repair needs. The human studies reviewed here do not establish clinical efficacy of a defined miRNA mimic or inhibitor in DFUs. Further translation requires miRNA profiling over time, assessment of the wound's biological stage, and delivery to the relevant cells during the appropriate repair window.