Diabetic neuropathy (DN) and impaired wound healing in diabetic foot ulcers(DFUs) are major complications of diabetes mellitus, driven by complex molecularmechanisms, including epigenetic modifications. Recent researc...Diabetic neuropathy (DN) and impaired wound healing in diabetic foot ulcers(DFUs) are major complications of diabetes mellitus, driven by complex molecularmechanisms, including epigenetic modifications. Recent research highlights therole 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 andwound healing outcomes. Genome-wide DNA methylation studies reveal acceleratedepigenetic aging and metabolic memory effects in DN, contributing tosensory neuron dysfunction and neuropathic pain. Epigenetic dysregulation ofinflammatory mediators such as Toll-like receptors and the Nod-like receptorfamily, pyrin domain-containing 3 inflammasome further exacerbates neuronaldamage and delays wound healing. Additionally, histone deacetylases play apivotal 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 epigeneticcrosstalk between DN and DFUs. Several miRNAs, including miR-146a-5p and miR-518d-3p, are implicated inneuropathy severity, while lncRNAs such as nuclear enriched abundant transcript 1 modulate angiogenesis andwound repair. Cellular reprogramming of DFU fibroblasts has also been shown to induce pro-healing miRNAsignatures, offering potential therapeutic avenues. Furthermore, recent whole-genome and transcriptomic analysesof DFU-derived monocytes and Charcot foot lesions reveal unique epigenetic signatures that may serve as biomarkersfor early detection and personalized interventions. This epigenetic interplay between DN and DFUpathogenesis not only enhances our knowledge of disease mechanisms but also opens avenues for targetedepigenetic therapies to improve clinical outcomes.展开更多
文摘Diabetic neuropathy (DN) and impaired wound healing in diabetic foot ulcers(DFUs) are major complications of diabetes mellitus, driven by complex molecularmechanisms, including epigenetic modifications. Recent research highlights therole 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 andwound healing outcomes. Genome-wide DNA methylation studies reveal acceleratedepigenetic aging and metabolic memory effects in DN, contributing tosensory neuron dysfunction and neuropathic pain. Epigenetic dysregulation ofinflammatory mediators such as Toll-like receptors and the Nod-like receptorfamily, pyrin domain-containing 3 inflammasome further exacerbates neuronaldamage and delays wound healing. Additionally, histone deacetylases play apivotal 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 epigeneticcrosstalk between DN and DFUs. Several miRNAs, including miR-146a-5p and miR-518d-3p, are implicated inneuropathy severity, while lncRNAs such as nuclear enriched abundant transcript 1 modulate angiogenesis andwound repair. Cellular reprogramming of DFU fibroblasts has also been shown to induce pro-healing miRNAsignatures, offering potential therapeutic avenues. Furthermore, recent whole-genome and transcriptomic analysesof DFU-derived monocytes and Charcot foot lesions reveal unique epigenetic signatures that may serve as biomarkersfor early detection and personalized interventions. This epigenetic interplay between DN and DFUpathogenesis not only enhances our knowledge of disease mechanisms but also opens avenues for targetedepigenetic therapies to improve clinical outcomes.
