Diabetic
wounds represent a formidable challenge in the clinical management of
diabetes mellitus, markedly diminishing the patient's quality of life. These
wounds arise from a multifaceted etiology, with the pathophysiological underpinnings remaining elusive and complex. Diabetes precipitates neuropathies and vasculopathies in the lower extremities, culminating in
infections, ulcerations, and extensive tissue damage. The hallmarks of non-healing diabetic
wounds include senescence, persistent
inflammation, heightened apoptosis, and attenuated cellular proliferation. The TP53 gene, a pivotal
tumor suppressor frequently silenced in human
malignancies, orchestrates cellular proliferation, senescence, DNA repair, and apoptosis. While p53 is integral in cell cycle regulation, its role in initial tissue repair appears to be deleterious. In typical cutaneous
wounds, p53 levels transiently dip, swiftly reverting to baseline. Yet in diabetic
wounds, protracted p53 activation impedes healing via two distinct pathways: i) activating the p53-p21-
Retinoblastoma (RB) axis, which halts the cell cycle, and ii) upregulating the cGAS-
STING and
nuclear factor-kappaB (NF-κB) cascades, instigating ferroptosis and pyroptosis. Furthermore, p53 intersects with various metabolic pathways, including glycolysis, gluconeogenesis, oxidative phosphorylation, and autophagy. In diabetic
wounds, p53 may drive metabolic reprogramming, thus potentially derailing macrophage polarization. This review synthesizes case studies investigating the therapeutic modulation of p53 in diabetic
wounds care. In summation, p53 modulates chronic
inflammation and cellular aging within diabetic cutaneous
wounds and is implicated in a novel cell death modality, encompassing ferroptosis and pyroptosis, which hinders the reparative process.