Sanusi KO, Asiwe JN, Sulaimon FA, Bashar F, Yusuf SK, Abdulkadir HO. Diabetic neuropathy and wound healing: An update on epigenetic crosstalk. World J Diabetes 2025; 16(11): 110428 [DOI: 10.4239/wjd.v16.i11.110428]
Corresponding Author of This Article
Kamaldeen Olalekan Sanusi, PhD, Head, Lecturer, Department of Human Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Al-Hikmah University, Adewole Estate, Adeta Road, Kwara State, P.M.B. 1601, Ilorin 240244, Nigeria. sanusikamaldeen@yahoo.com
Research Domain of This Article
Physiology
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Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Kamaldeen Olalekan Sanusi, Department of Human Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Al-Hikmah University, Ilorin 240244, Nigeria
Jerome Ndudi Asiwe, Department of Physiology, Faculty of Basic Medical Sciences, Delta State University, Abraka 330105, Nigeria
Fatimo Ajoke Sulaimon, Department of Anatomy, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin 240003, Nigeria
Farida Bashar, Department of Biochemistry and Molecular Biology, Faculty of Chemical and Life Sciences, Usmanu Danfodiyo University, Sokoto 840001, Nigeria
Suleiman Kolawole Yusuf, Department of Veterinary Physiology and Biochemistry, Faculty of Veterinary Medicine, University of Ilorin, Ilorin 240003, Nigeria
Hawau Olaide Abdulkadir, Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin 240003, Nigeria
Author contributions: Sanusi KO participated in the conception of the study; Sanusi KO, Asiwe JN, Sulaimon FA, Bashar F, Yusuf SK, and Abdulkadir HO wrote the original draft of the manuscript; All authors revised and approved the final version of the manuscript.
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Kamaldeen Olalekan Sanusi, PhD, Head, Lecturer, Department of Human Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Al-Hikmah University, Adewole Estate, Adeta Road, Kwara State, P.M.B. 1601, Ilorin 240244, Nigeria. sanusikamaldeen@yahoo.com
Received: June 6, 2025 Revised: August 2, 2025 Accepted: September 26, 2025 Published online: November 15, 2025 Processing time: 161 Days and 9.8 Hours
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.
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.
Citation: Sanusi KO, Asiwe JN, Sulaimon FA, Bashar F, Yusuf SK, Abdulkadir HO. Diabetic neuropathy and wound healing: An update on epigenetic crosstalk. World J Diabetes 2025; 16(11): 110428
Diabetic neuropathy (DN) presents a formidable challenge in diabetes care, affecting approximately 50% of patients with diabetes with debilitating symptoms such as pain, sensory loss, and diabetic foot ulcers (DFUs)[1]. These complications stem from neuronal damage triggered by a hyperglycemic milieu, oxidative stress, and chronic inflammation. Despite advancements in glycemic control therapies, DN continues to exact a heavy toll, often leading to severe outcomes such as amputation and diminished quality of life[2]. Current research endeavors are keenly focused on uncovering alternative pathways and biomarkers to deepen our understanding of DN, potentially paving the way for innovative treatments amidst existing therapeutic limitations.
Emerging evidence places epigenetic regulation, heritable modifications to DNA and chromatin, at the center of this interplay. For example, sustained hyperglycemia imprints “metabolic memory” via DNA methylation and histone marks, locking in pro-inflammatory gene expression even after glycemic control[3]. These epigenetic marks often occur near or within genes for non-coding RNAs (microRNAs [miRNAs], long non-coding RNAs [lncRNAs], circular RNAs [circRNAs]), creating an integrated network of regulation[4].
In this review we link each epigenetic layer to DN and DFU pathogenesis, emphasizing how DNA methylation, histone modifications, and non-coding RNAs jointly reinforce neuropathy and delayed healing. Each section previews the key mechanisms and concludes with implications for therapy.
EPIGENETIC ALTERATIONS IN DN
Epigenetics refers to heritable changes in gene expression that occur without altering the underlying DNA sequence. These changes are orchestrated through a variety of mechanisms, primarily DNA methylation, histone modifications, and non-coding RNAs, that regulate chromatin structure and gene accessibility. Unlike genetic mutations, epigenetic marks are dynamic and reversible, allowing cells to adapt their transcriptional programs in response to metabolic, environmental, and inflammatory cues[5].
In the context of diabetes and its complications, epigenetic dysregulation plays a central role in perpetuating pathological states such as inflammation, oxidative stress, and impaired repair capacity (Figure 1). A phenomenon of “metabolic memory” underscores the persistence of diabetic complications even after glycemic normalization-an effect increasingly attributed to stable epigenetic reprogramming of key cell types. Recent studies in human patients and models provide robust support for many factors[3,6].
Figure 1 Integrated epigenetic network in diabetic complications.
This schematic illustrates the interplay between major epigenetic modifications (DNA methylation, histone modifications, and non-coding RNAs) in driving chronic inflammation, oxidative stress, impaired neurovascular repair, and tissue degeneration. These processes contribute to the development and persistence of diabetic neuropathy (DN) and diabetic foot ulcers (DFUs) by disrupting key protective pathways and promoting pathological gene expression.
Role of DNA methylation in DN
DNA methylation at promoter CpG islands has been associated with gene repression, and studies have shown the involvement of this epigenetic mark in the context of diabetes and its related complications. Gastoł et al[7] elucidated that hypermethylation of ninjurin 2 and hypomethylation of claudin-4 in peripheral blood were associated with reduced expression and likely impaired neural regeneration. These genes regulate neurite outgrowth and Schwann cell tight junctions, respectively, which are processes essential for peripheral nerve integrity. Although brain-specific serine/threonine kinase 2 methylation changes were observed, their functional relevance could not be confirmed due to limited expression in peripheral blood, highlighting the need for tissue-contextual validation.
Beyond peripheral blood, tissue-specific studies have also provided direct mechanistic evidence of DNA methylation in DN. Guo et al[8] conducted genome-wide methylation and transcriptomic analyses of human sural nerve biopsies from patients with type 2 diabetes mellitus (T2DM) with diabetic peripheral neuropathy (DPN). They identified more than 2000 differentially methylated CpG sites and nearly 1000 differentially expressed genes, many of which clustered by glycated hemoglobin (HbA1c) levels, underscoring the impact of chronic hyperglycemia on epigenetic remodeling. Notably, genes involved in immune signaling, extracellular matrix remodeling, oxidative stress, and axon guidance (e.g., mitogen-activated protein kinase [MAPK] 8 interacting protein 3, Thy-1 cell surface antigen, phospholipase Cγ2) were both differentially methylated and expressed, illustrating functional epigenetic regulation beyond promoter regions[8]. Moreover, enriched pathways such as phosphoinositide 3-kinase/Akt signaling, extracellular matrix (ECM)-receptor interaction, and axon guidance were all shown to be under epigenetic control, providing a molecular basis for how sustained metabolic dysfunction leads to nerve degeneration[8].
In addition, by comparing subjects with progressive nerve degeneration to those showing nerve regeneration, they identified 3460 differentially methylated CpG sites enriched in genes linked to nervous system development, neuron differentiation, axon guidance, glycerophospholipid metabolism, and MAPK signaling pathways[9]. It was found that hypermethylation and hypomethylation were distributed across various genomic regions, with a notable proportion in intronic and intergenic regions rather than promoter regions, a pattern increasingly recognized in metabolic diseases. Differential methylation of genes like dihydropyrimidinase like 2 (involved in axon growth) and miR3138 (a miRNA potentially regulating nerve repair genes) was validated, suggesting that altered methylation states could impact nerve regenerative capacity by modulating gene expression[9]. These findings align with the emerging view that epigenetic alterations, rather than fixed genetic mutations, critically mediate environmental and metabolic risk factors for neuropathy.
Similarly, it was demonstrated that whole-genome leukocyte DNA methylation levels were significantly reduced in patients with DPN compared to non-DPN individuals. Lower methylation correlated strongly with neuropathy severity (measured by the Toronto Clinical Scoring System), duration of diabetes, and renal function estimated glomerular filtration rate, but not with acute glycemic control markers (e.g., HbA1c). Importantly, methylation levels did not significantly differ by nephropathy status, suggesting some specificity of hypomethylation to neural complications rather than reflecting general diabetic deterioration[10].
Thus, DNA methylation signatures in both blood and nerve tissue reflect persistent epigenetic changes not explained by current glycemic indices alone. The fact that methylation patterns correlate more strongly with neuropathy severity and chronicity than with glucose levels suggests that DPN is fundamentally a disorder of disrupted epigenomic homeostasis.
Role of histone and chromatin modifications in DN
Diabetes fundamentally reprograms chromatin architecture in both neural and dermal tissues, contributing to persistent inflammation, oxidative stress, and impaired regeneration. One major mechanism involves dysregulation of histone modifiers, which are enzymes that regulate chromatin accessibility via post-translational modifications such as acetylation and methylation.
In DFUs, macrophages extracted from wound tissue exhibit increased expression of the histone H3 Lysine 27 (H3K27) demethylase KDM6B (also known as JMJD3) and the H3K4 methyltransferase mixed-lineage leukemia 1 gene. These enzymes promote transcription of pro-inflammatory genes, thus sustaining a chronic inflammatory microenvironment[11]. Meanwhile, diabetic dermal cells show reduced histone acetylation at promoters of key antioxidant genes, such as superoxide dismutase 3, which compromises reactive oxygen species detoxification[12].
Global histone profiling in DFU tissues has revealed increased expression of class I histone deacetylases (HDAC1, HDAC3, HDAC4, HDAC11), whose upregulation negatively correlates with Nrf2, a master regulator of antioxidant responses[13]. Conversely, protective HDACs of the sirtuin (SIRT) family, including SIRT1, SIRT2, SIRT6, and SIRT7, are significantly downregulated in chronic wounds, further contributing to redox imbalance and impaired healing. Targeted inhibition of class I HDACs while preserving sirtuin activity (e.g., using selective HDAC inhibitors or SIRT1 activators) has shown promise in reactivating Nrf2 signaling and accelerating wound repair[14,15].
Similar epigenetic alterations are observed in DN. Increased HDAC1 and HDAC2 Levels in peripheral neurons of diabetic models are associated with the downregulation of neurotrophic factors essential for axonal maintenance and repair[16]. In addition, key ATP-dependent chromatin remodelers, such as the SWI/SNF complex subunit BRG1, are suppressed in diabetic keratinocytes, leading to impaired cell migration and differentiation, key barriers to wound re-epithelialization[17]. These findings emphasize that histone modifiers and chromatin remodeling enzymes function as both biomarkers and effectors of diabetes-induced tissue damage.
Collectively, aberrant histone acetylation and methylation constitute a critical molecular link among sustained hyperglycemia, chronic inflammation, and impaired tissue repair in both neurons and skin. These observations support the growing interest in pharmacologically targeting HDACs, sirtuins, and chromatin remodelers to restore epigenetic homeostasis and functional recovery in DN and DFUs.
Role of non-coding RNAs in DN
While the impact of DNA methylation and histone modifications on DN has been emphasized, recent studies highlight that non-coding RNAs, particularly miRNAs, lncRNAs, and circRNAs, are equally pivotal in shaping epigenetic landscapes. These RNA species do not merely operate in parallel; they often intersect with and regulate classical epigenetic mechanisms, such as DNA methyltransferase expression (e.g., DNA-methyltransferase 1 [DNMT1] regulation by miR-29) and histone acetylation pathways (e.g., SIRT1 modulation by miR-132 and lncRNAs). Moreover, non-coding RNAs can respond to, or themselves induce, methylation and chromatin remodeling at target loci, thus reinforcing disease-driving transcriptional programs. The following sections outline how non-coding RNAs act as both effectors and modulators of the epigenetic alterations described earlier, with emphasis on their roles in inflammation, oxidative stress, nerve regeneration, and wound healing.
Inflammation/oxidative miRNAs: In DN, protective miR-146a is downregulated in dorsal root ganglia (DRG), unleashing nuclear factor kappa B (NF-κB)-driven inflammation. Conversely, miR-155 shows context-dependent dysregulation: It is upregulated in DFUs, where its inhibition restores fibroblast growth factor 7 (FGF7) and reduces inflammation, but is reported as “down” in some DN models where it normally represses Nrf2[6]. Likewise, miR-29 (often increased in DN) targets Nrf2, and its aberrant levels perturb antioxidant defenses. Inflammatory signaling is further modulated by these miRNAs via suppressor of cytokine signaling 1 and Toll-like receptor (TLR)/NF-κB pathways[6]. Overall, miR-146a, miR-155, miR-29, and related miRNAs form a tug-of-war that regulates inflammation and redox balance in DN/DFU[18,19].
Neuro-regenerative miRNAs: Other miRNAs govern neuronal survival and regeneration. For example, reduced miR-132 (which normally supports synaptic plasticity) worsens DN pathology[20]. MiR-124 helps Schwann cell function and regeneration[21]. In a mouse DN model, let-7i and miR-341 were identified as causal: Delivering let-7i mimics or anti-miR-341 oligonucleotides improved sensory function and nerve conduction without changing glucose[22]. This “epigenetic therapy” reversed neuropathy via RNA pathways, illustrating how miRNA modulators can bypass metabolic defects.
LncRNAs: LncRNAs also tune DN outcomes. Metastasis-associated lung adenocarcinoma transcript 1 (increased in DN) promotes Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome activity and aberrant splicing of axonal maintenance genes. Fibrosis-linked HOTAIR enhances transforming growth factor beta (TGF-β)/Smad signaling in nerves[23]. Conversely, the lncRNA brain-derived neurotrophic factor-antisense (BDNF-AS) (antisense to BDNF) and maternally expressed gene 3 (MEG3) disrupt neurotrophic support and Schwann cell survival[24,25]. Other lncRNAs (e.g., growth arrest-specific 5, FOXF1 adjacent non-coding developmental regulatory RNA, and LOC100506036) epigenetically modulate chromatin and methylation to influence inflammatory genes. A genome-wide screen found lncRNAs like LINC00324, DHRS4-AS1, and NONRATT021972 with altered expression in DN[26-29]; these are linked to histone marks, methylation, and receptors (P2X purinoceptor 3/7) in pain pathways[30].
circRNAs: CircRNAs also reportedly contribute to inflammation in DN. CircHIPK3 sponges miR-30a, and promotes endothelial dysfunction and inflammation in DN[31], whereas another type of circRNA, CircRNA_000203, exacerbates fibrosis by sequestering miR-26b-5p[32]. Furthermore, the circRNAs circ_0002538 plays a protective role in DPN by promoting nerve regeneration and myelination. In patients with DPN, reduced circ_0002538 and plasmolipin (PLLP) levels correlate with axonal loss despite intact myelin sheaths. Mechanistically, circ_0002538 upregulates PLLP, a key protein in nerve repair and myelination by acting as a sponge for miR-138-5p, which normally suppresses PLLP expression. In DPN mice, circ_0002538 enhances peripheral nerve function through this miR-138-5p/PLLP axis, improving Schwann cell myelination. These findings suggest circ_0002538 as a potential therapeutic target for restoring nerve damage in DN. Further highlighting the role of circRNA in DN is the study of Zhang et al[33], which revealed widespread circRNA alterations in diabetic DRG with circRNA.4614 being significantly upregulated in the DRG of diabetic mice compared to the wild type.
Thus, non-coding RNAs form an interlinked regulatory web. miRNAs and lncRNAs modulate the same pathways identified under DNA methylation and histone control (e.g., NF-κB, TGF-β, Nrf2). Many DN/DFU studies now show that correcting a single miRNA can have potent effects on multiple downstream genes. This supports the feasibility of RNA-based therapeutics (miRNA mimics/antagomirs, lncRNA modulators) in DN. Indeed, early trials in DFU models (e.g., small interfering RNA [siRNA] against WT1-associating protein [WTAP]/DNMT1) have shown improved wound angiogenesis (Table 1).
Table 1 Key epigenetic regulators in diabetic neuropathy.
Epigenetic factor
Evidence (model)
Clinical relevance/notes
Influence on DN
Influence on DFU
Interaction DN→DFU
Strength of evidence
DNMT1
High. Upregulated in diabetic macrophages/fibroblasts; also modulated by WTAP in HUVECs[3]
EPIGENETIC DYSREGULATION IN DFUS AND WOUND HEALING
DFUs exhibit many of the same epigenetic derangements, with DFU-specific rewiring. Increasing evidence indicates that beyond metabolic insults, epigenetic reprogramming plays a central role in perpetuating these pathological features. Epigenetic mechanisms not only sustain harmful gene expression profiles but also lock DFU cells into a maladaptive state, even when glycemic control is restored. The following sections outline how these epigenetic aberrations converge to disrupt tissue regeneration in DFUs and the potential molecular targets for reversing the epigenetic scars that underlie chronic non-healing wounds.
DNA methylation in DFUs
Fibroblasts from chronic DFUs retain a “memory” of hyperglycemia as global hypomethylation, even after weeks in normal glucose. Hypermethylation of pro-healing genes (FGF1, collagen type IV alpha 1 [COL4A1], and urokinase-type plasminogen activator) was observed, while others (e.g., matrix metalloproteinase-9) became hyperactive via translocation methylcytosine dioxygenase (TET)-mediated demethylation. This persistent methylation signature impairs angiogenesis and matrix remodeling independently of current glycemia[34].
Histone modifiers in DFUs
SIRT1, a HDAC that activates antioxidant defenses, is downregulated in DFU tissue. Lower SIRT1 mRNA in patients with DFU correlates with reduced catalase and high tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6), high mobility group box 1 and advanced glycation end products. In parallel, class I HDACs (1, 3, 4, 11) are elevated in DFU wounds, repressing Nrf2-regulated antioxidant genes[13,35]. Thus, DFUs have a double-hit: Loss of protective deacetylation (SIRTs) and gain of deleterious HDAC activity. Selective inhibition of pathogenic HDACs (while preserving SIRT1) could therefore rebalance redox regulation.
miRNAs and lncRNAs in DFUs
Certain miRNAs are key. miR-27b was identified as an upstream regulator of Nrf2: Its suppression (and that of Nrf2 itself) in DFU endothelial cells weakens angiogenesis. Notably, pharmacologic activation of Nrf2 (via pterostilbene or resveratrol) not only restores antioxidant gene expression but also upregulates miR-27b, revealing a feedback loop that could be exploited. Additionally, the lncRNA nuclear enriched abundant transcript 1 (NEAT1) forms a critical axis with miR-146a-5p: Low NEAT1 in DFU tissue permits miR-146a-5p to rise and suppress MafG (an angiogenic transcription factor), crippling vessel growth[36]. Restoring NEAT1 or blocking miR-146a-5p reverses this defect and enhances angiogenesis[37,38]. These examples show that DFU pathology hinges on multi-layered epigenetic loops. This critical regulatory axis emphasizes the multifaceted epigenetic controls over wound healing and identifies novel molecular targets for intervention, rounding out the intricate picture of how transcriptional, post-transcriptional, and epigenetic mechanisms intertwine to govern DFU progression as illustrated in Figure 2.
Figure 2 Epigenetic regulations in diabetic foot ulcer pathogenesis and healing.
SIRT1 downregulation leads to elevated pro-inflammatory mediators and oxidative stress, which impairs wound healing. Persistent DNA hypomethylation, despite normoglycemia, sustains metabolic memory and represses key reparative genes (e.g., collagen type IV alpha 1 [COL4A1], plasminogen activator, tissue type 1 [PLAT1], and fibroblast growth factor 1 [FGF1]). Reprogramming fibroblasts through modulation of microRNAs (e.g., miR-26b-5p, let-7c, miR-196a-5p) restores pro-repair gene expression, improves redox balance, and promotes vascular repair. Additionally, targeting the histone deacetylase (HDAC)–sirtuin axis via selective HDAC inhibition and enhancing Nrf2 signaling refines therapeutic strategies. Suppression of long non-coding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) and modulation of the miR-46a-5–MafG axis further improve angiogenesis. Together, these insights identify promising therapeutic avenues.
Cell reprogramming
Importantly, diabetic fibroblasts can be “reset.” Induced pluripotent stem cell reprogramming of DFU fibroblasts remodeled their miRNA profile: Levels of let-7c, miR-26b-5p, miR-196a-5p were reduced, which upregulated target genes (plasminogen activator, tissue type [PLAT] and COL4A1) that improve ECM remodeling and migration[26]. This demonstrates that even entrenched DFU epigenomes retain plasticity. In essence, DFU cells harbor reversible epigenetic scars that can be targeted to restore healing.
EPIGENETIC CROSSTALK BETWEEN NEUROPATHY AND WOUND HEALING
The pathophysiology of DN and DFUs is not merely parallel but mutually reinforcing, with epigenetic modifications serving as a mechanistic bridge. In DN, DNA methylation-induced silencing of neurotrophic genes such as BDNF and nerve growth factor, along with lncRNAs like BDNF-AS and MEG3, impairs neuronal regeneration and Schwann cell survival[24,25]. Loss of protective innervation reduces detection of microtrauma and disrupts neuropeptide signaling (e.g., calcitonin gene-related peptide and substance P), both of which are critical for vasodilation, immune cell recruitment, and keratinocyte proliferation during wound healing[2,8,9]. As a result, neuropathy-driven epigenetic changes predispose patients to chronic, non-healing ulcers. Conversely, persistent DFUs generate a pro-inflammatory milieu enriched with cytokines such as TNF-α and IL-1β, which drive HDAC1/3 overexpression in wound macrophages[13,35]. These histone modifications not only sustain local oxidative stress but also aggravate systemic redox imbalance, a mechanism linked to neuronal degeneration in DN[16]. Importantly, several non-coding RNAs, including miR-146a and lncRNA NEAT1, operate at this intersection: Their dysregulation simultaneously promotes neuroinflammation[18,19] and impairs angiogenesis in DFUs[36]. This bidirectional epigenetic dialogue indicates that neuropathy-induced changes in nerve-immune signaling worsen wound repair, while DFU-related inflammatory reprogramming accelerates neural injury. Collectively, these insights frame DN and DFUs as interconnected complications sustained by shared epigenetic “memory,” underscoring the need for therapeutic strategies that jointly target neuroprotection and wound regeneration[39,40].
EPIGENETIC EFFECTS ON INFLAMMATION AND NEUROPATHY
Chronic inflammation is implicated in the development of DN, and recent research has emphasized the involvement of epigenetic modifications in the control of inflammatory reactions enhancing neuropathic pain. Epigenetic changes and gene mutations both play a role in the pathophysiology of DN, and it is significant in relation to developing the disease and therapies[39,40].
Polymorphisms in key immune-regulatory genes, including those coding for DNMTs and inflammatory cytokine receptors, play a determining role in susceptibility to neuropathy. For example, mutations in the DNMT1 gene have been linked to a higher risk of cardiovascular autonomic neuropathy in patients with T1DM[41]. The DNMT1 gene, which plays a significant role in the process of DNA methylation, has the potential to modify the expression of pro-inflammatory genes under hyperglycemia, thus leading to inflammation and neuronal injury. Specifically, the minor allele of the single nucleotide polymorphism rs11085721 in the DNMT1 gene is associated with higher cancer susceptibility in women, an inherited susceptibility that promotes epigenetic alterations[41].
Moreover, epigenetic alterations, including methylation of DNA, histone modification, and regulation of non-coding RNAs, have a pivotal position in the regulation of the inflammatory reaction in DN. Especially, the process of DNA methylation, along with the activities of DNA demethylases such as ten-eleven TETs, plays a significant role in regulating the expression of inflammatory cytokines and inflammasomes, which are pivotal to the development of DN[40]. Empirical evidence has established that the activation of the NLRP3 inflammasome within the DRG is a key player in DN -associated pain hypersensitivity. TET2, a DNA demethylase involved in the regulation of gene expression through the demethylation of DNA in response to glucose elevation, controls this pathway[40]. In diabetic murine models, TET2 upregulation in DRG leads to DNA demethylation, further initiating the TXNIP/NLRP3 inflammasome signaling pathway and aggravating pain sensitivity[40]. Such epigenetic regulation for NLRP3 inflammasome activation is a key mechanism underlying the progression of diabetic neuropathic pain. Additionally, research on the epigenetic control of TLR2 in T2DM has also offered additional information regarding the interplay between the epigenetic and genetic factors influencing inflammation and DN. TLR2 is a key component of the immune response whose downregulation in diabetic wounds has been associated with defective wound healing and exaggerated inflammation. Of interest, both genetic and epigenetic alterations in TLR2 expression have been described in DFU, in which methylation of the promoter region impairs the capacity of the receptor to mediate inflammatory responses, which may lead to sustained inflammation and chronic wound development[39]. The epigenetic alteration of TLR2 observed suggests the potential that inflammatory responses associated with DN are augmented by gene silencing through DNA methylation, with resultant inappropriate immune modulation and impaired tissue repair.
Additionally, epigenetic memory play a role in inflammation and DN. The phenomenon of metabolic memory, in which hyperglycemia causes long-term epigenetic modifications even after normalization of blood glucose levels, has been an area of growing interest in the pathogenesis of diabetic complications. Epigenetic modifications, can lead to chronic DN and wound healing impairment as a consequence of prolonged inflammation. It has been proven through research that long-term high blood glucose in patients with T2DM results in the modification of immune system genes by DNA methylation, thereby promoting the inflammatory pathways responsible for neuropathic pain[39]. These modifications are usually inheritable, meaning they can be transmitted through cell division, thereby perpetuating a continuous process of inflammation and neural degeneration[39]. Pro-inflammatory cytokines like TNF-α and IL-1β are upregulated in the context of DN and are key to initiating nociceptive transmission and enhancing neuroinflammation (Figure 3). Thus, the genetic polymorphisms and epigenetic modifications that regulate the expression levels of these cytokines may be useful targets for therapeutic strategies to modulate inflammation and prevent or mitigate neuropathic pain in diabetics[39,40].
Figure 3 Impact of DNA methylation on inflammatory responses in diabetic neuropathy.
This schematic illustrates the role of aberrant DNA methylation in promoting inflammatory signaling pathways implicated in diabetic neuropathy. In somatic cells (muscle, adipocytes, epithelial), hyperactivation of DNA methylation machinery, including DNA-methyltransferase 1 (DNMT1) and other DNMTs, leads to increased chromatin methylation. The polycomb repressive complex 2 (PRC2) and S-adenosylmethionine (SAM) facilitate histone methylation (Me3) at key regulatory loci, repressing transcriptional activity by RNA polymerase II (RNAPII). This epigenetic repression alters immune signaling pathways, particularly by upregulating inflammatory cytokine receptors (e.g., Janus kinase/signal transducer and activator of transcription signaling), which in turn enhances transcription of pro-inflammatory cytokine genes, including tumor necrosis factor (TNF), interleukin 1 (IL-1), and IL-6. The persistent expression of these inflammatory mediators contributes to chronic neuroinflammation and the progression of diabetic neuropathy.
EPIGENETICS IN DIABETIC CHARCOT FOOT AND OTHER MICROVASCULAR COMPLICATIONS
Charcot foot (CF) is an uncommon but serious complication of diabetes. It significantly raises the risk of soft tissue infections, foot ulcers, and even amputations[42], contributing to high levels of illness and death[43]. This condition most often affects people with diabetes who have advanced peripheral neuropathy, and in many cases, it also involves damage to the sympathetic nerves, which leads to increased blood flow and bone breakdown in the foot[44]. Patients with CF have a significantly reduced life expectancy by approximately 14.4 years[45]. The primary risk factor for CF is severe peripheral neuropathy, which causes loss of sensation and disrupts normal blood flow regulation. Research has outlined a clear pathway in which uncontrolled inflammation plays a key role. This involves the release of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6, which activate NF-B. This activation prompts precursor bone cells to develop into mature osteoclasts, ultimately leading to bone breakdown and structural deformities[46].
In a meta-analysis by Zhu et al[47], 151 miRNAs were identified as having altered expression in various cell types, blood, or tissues (e.g., liver, adipose tissue, pancreas, and muscle) in both human and animal models of T2DM. Of these, 51 were found to be significantly differentially expressed. The study highlighted eight specific miRNAs (miR-29a, miR-34a, miR-103, miR-107, miR-132, miR-142-3p, miR-144, and miR-375) as promising biomarkers for T2DM. The fact that these circulating miRNAs are present in bodily fluids means they can be identified, measured, and potentially used as biomarkers for disease[48]. Leeper and Coop[49] also found that miRNAs involved in epigenetic changes in diabetic ulcers include the depletion of miR-126, driven by and correlated with concomitant overexpression of miR-503 induced by the chronically elevated values of glycemia, which seems to play a relevant role. The increased expression of miR-503 Leads to a reduction of angiogenesis and a depletion of miR-126 Levels, which causes a concomitant reduction of the re-epithelialization process. The two mechanisms act synchronously, which impedes the healing process of the diabetic ulcer.
Additionally, miRNAs such as miR-518d-3p and miR-618 are upregulated in individuals with T1DM with chronic DN[41]. Essentially, research has highlighted miR-518 as a miRNA with potential regulatory effects on peroxisome proliferator-activated receptor alpha (PPARα)[50]. Experimental validation demonstrated that miR-518d binds to the 3’ untranslated region of PPARα mRNA, directly suppressing its expression. Notably, elevated levels of miR-518d in placental tissue have been associated with gestational diabetes, suggesting a possible mechanistic link[51]. The upregulation of miR-518d-3p may also serve as an indicator of widespread endothelial dysfunction in these individuals. Supporting this possibility, studies have shown that miR-518d-3p expression increases in human endothelial cells exposed to acrolein, an unsaturated aldehyde to provoke oxidative stress and inflammation[52] both of which are similarly promoted by hyperglycemia[53].
FUTURE DIRECTIONS
The intertwined nature of DN and DFU epigenetics demands integrated approaches. Future research should include large-scale multi-omic profiling (methylome, histone chromatin immunoprecipitation assay with sequencing, transcriptome including ncRNAs) in patient-derived tissues, to map these networks comprehensively. Comparative analysis of DFU subtypes (ischemic vs neuropathic) and time-course studies can reveal which epigenetic alterations precede complication onset. Importantly, interventional trials are needed. For example, selective HDAC inhibitors (isoform-specific HDAC6, class I vs SIRT activators) and DNMT1/m6A modulators should be tested for efficacy in wound healing or neuropathy models. Recent trials highlight both promise and pitfalls: VM202 (a hepatocyte growth factor-expressing plasmid) achieved significant pain reduction in DPN phase 3, whereas the HDAC6 inhibitor ricolinostat failed to improve neuropathic pain in DPN (although it was well tolerated)[54]. These mixed results underscore the challenges of translation.
TRANSLATIONAL OUTLOOK
Epigenetic therapies must overcome delivery and specificity hurdles. HDAC inhibitors often have broad effects; next-generation epi drugs should target specific isoforms or exploit nanoparticle delivery to wounds. Similarly, miRNA-based treatments (mimics or antagomirs) face issues of stability and off-targeting, but innovations in lipid nanoparticles and conjugates are promising. Recent successes in targeting RNA (e.g., siRNAs in other diseases) support feasibility. Combining epigenetic drugs with standard care (growth factors, debridement, and improved glycemic control) may be required. Crucially, any new therapy should be guided by biomarkers: For instance, circulating miR-146a or WTAP levels might identify patients most likely to benefit from a given epi drug. Overall, the goal is personalized, epigenetically informed care: Stratifying patients by epigenetic “fingerprint” and tailoring HDAC vs DNMT vs miRNA interventions accordingly.
CONCLUSION
DN and DFUs are driven not just by metabolic insult, but by a self-sustaining epigenetic network. Persistent DNA methylation changes, deregulated chromatin marks, and non-coding RNA circuits lock in inflammation and block repair. Understanding this crosstalk has already suggested novel targets (e.g., WTAP/DNMT1, specific miRNAs, HDACs) and shapes future research. We encourage studies that bridge bench and bedside, testing epi drugs in rigorous clinical trials, developing epigenetic biomarkers, and integrating omics data into predictive models. With diabetes on the rise, these epigenetic insights may finally enable therapies that halt neuropathy progression and accelerate wound healing.
Footnotes
Provenance and peer review: Invited article; Externally peer reviewed.
Peer-review model: Single blind
Corresponding Author's Membership in Professional Societies: Genetics Society of America; Physiological Society of Nigeria; African Society for Dental and Craniofacial Genetics.
Specialty type: Endocrinology and metabolism
Country of origin: Nigeria
Peer-review report’s classification
Scientific Quality: Grade A, Grade B, Grade C
Novelty: Grade B, Grade C
Creativity or Innovation: Grade B, Grade C
Scientific Significance: Grade A, Grade D
P-Reviewer: Hrgović Z, DM, MD, Senior Researcher, Croatia; Hwu CM, MD, Professor, Taiwan; Zhao Z, PhD, China S-Editor: Qu XL L-Editor: Filipodia P-Editor: Zhao S
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