Diabetic neuropathy and wound healing: An update on epigenetic crosstalk

Abstract

Diabetic neuropathy (DN) and impaired wound healing in diabetic foot ulcers (DFUs) are major complications of diabetes mellitus, driven by complex molecular mechanisms, including epigenetic modifications. Recent research highlights the role of epigenetic markers including DNA methylation, histone modifications, and non-coding RNAs in regulating inflammatory responses, neuronal degeneration, and tissue repair. This review explores the epigenetics of DN and DFUs, emphasizing key regulatory pathways that influence disease progression and wound healing outcomes. Genome-wide DNA methylation studies reveal accelerated epigenetic aging and metabolic memory effects in DN, contributing to sensory neuron dysfunction and neuropathic pain. Epigenetic dysregulation of inflammatory mediators such as Toll-like receptors and the Nod-like receptor family, pyrin domain-containing 3 inflammasome further exacerbates neuronal damage and delays wound healing. Additionally, histone deacetylases play a pivotal role in oxidative stress regulation via the Nrf2 pathway, which is critical for both neuronal protection and angiogenesis in DFUs. Non-coding RNAs, particularly microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs, are emerging as central regulators of the epigenetic crosstalk between DN and DFUs. Several miRNAs, including miR-146a-5p and miR-518d-3p, are implicated in neuropathy severity, while lncRNAs such as nuclear enriched abundant transcript 1 modulate angiogenesis and wound repair. Cellular reprogramming of DFU fibroblasts has also been shown to induce pro-healing miRNA signatures, offering potential therapeutic avenues. Furthermore, recent whole-genome and transcriptomic analyses of DFU-derived monocytes and Charcot foot lesions reveal unique epigenetic signatures that may serve as biomarkers for early detection and personalized interventions. This epigenetic interplay between DN and DFU pathogenesis not only enhances our knowledge of disease mechanisms but also opens avenues for targeted epigenetic therapies to improve clinical outcomes.

Keywords: Diabetic neuropathy; Wound healing; Diabetic foot ulcers; Epigenetics; Inflammation; Metabolic memory; Precision medicine

Core Tip: Diabetic neuropathy and impaired wound healing in diabetic foot ulcers are significant complications of diabetes. They are driven by complex molecular mechanisms involving epigenetic modifications such as DNA methylation, histone modifications, and non-coding RNAs. These epigenetic alterations contribute to inflammatory responses, neuronal degeneration, and disrupted tissue repair, with "metabolic memory" causing long-lasting molecular imprints even after blood glucose normalization. This emerging understanding of the epigenetic interplay provides a comprehensive framework for disease development and opens new avenues for targeted therapies and biomarkers to improve clinical outcomes beyond traditional glucose-centric views.