Function of epigenetic modifications in wound healing and potential therapies (Review)

Abstract

Wound healing is a highly coordinated physiological process, which is essential for restoring the structural and functional integrity of damaged tissues. The present review explores the multifaceted roles of epigenetic modifications in wound healing and their potential as therapeutic targets. Epigenetic mechanisms, including DNA methylation, histone modifications, regulation by non-coding RNAs (ncRNAs) and RNA methylation, influence the speed and quality of wound repair by regulating gene expression, cell function and intercellular signaling. During the hemostasis phase, DNA methylation of genes such as platelet endothelial aggregation receptor 1 can impact platelet function, while histone methylation and acetylation serve critical roles in modulating inflammation and fibroblast activation. ncRNAs, such as microRNAs and long ncRNAs, regulate cell proliferation, collagen deposition and scar formation. N⁶-methyladenosine modifications, a type of RNA methylation, impact autophagy and fibrosis through their interaction with YTH domain family proteins. Key epigenetic regulators influence wound healing outcomes, providing valuable insights for the development of novel therapeutic strategies. However, challenges remain in translating these findings into clinical applications due to the complexity of epigenetic networks and the need for precise regulatory tools. Future research should focus on elucidating the cell-specific and spatiotemporal regulatory mechanisms of epigenetic modifications in wound healing, and exploring their potential as therapeutic targets for reducing scar formation and preventing chronic wounds.

1. Introduction

As the primary defense barrier of the organism, the skin is continuously exposed to diverse environmental challenges, including harmful ultraviolet radiation, pathogen invasion and excessive water evaporation (1,2). To counteract injuries, organisms have developed sophisticated cellular and tissue repair mechanisms through evolution (3–5). The study of wound healing mechanisms, which has persisted for over a century, remains a pivotal field in regenerative medicine and pathology. Wound healing is a highly coordinated physiological process aimed at restoring the structural and functional integrity of damaged tissues. This process is typically divided into four interconnected and tightly regulated phases: Hemostasis, inflammation, proliferation and remodeling (6–8). During this process, multiple cell types, including fibroblasts, keratinocytes, endothelial cells and immune cells, collaborate to promote wound closure through mechanisms such as cell migration, proliferation, extracellular matrix (ECM) deposition and tissue remodeling (8,9). However, the delicate balance of wound healing is highly susceptible to disruption by internal and external factors, such as infection, hyperglycemic conditions (such as diabetes) or autoimmune diseases, which can lead to delayed healing, aberrant repair or even pathological scar formation (10–13). The global rise in aging populations and the increasing prevalence of chronic diseases (such as diabetes and cardiovascular disorders) have increased the incidence of refractory wounds (such as diabetic foot ulcers, pressure injuries and venous ulcers), posing a major public health challenge (14,15). Epidemiological studies indicate that 1–2% of the population in developed countries may suffer from chronic wounds during their lifetime, while patients with diabetic foot ulcers face a 15–25% risk of amputation (16–18). These conditions not only severely impair the quality of life of patients but also impose substantial socioeconomic burdens (19). Consequently, elucidating the molecular mechanisms underlying wound healing and developing targeted interventions to correct cellular dysfunction and optimize repair processes has profound clinical significance.

Epigenetics is the study of heritable changes in gene expression that do not involve alterations in DNA sequences but are achieved through mechanisms such as DNA methylation, histone modification, regulation by non-coding RNAs (ncRNAs) and RNA modification (20,21). The concept of epigenetics can be traced back to the early 20th century, and with the development of molecular biology techniques, research in epigenetics has been continuously deepened (22). DNA methylation and histone modification were the earliest identified epigenetic modifications, and the regulatory roles of ncRNAs have also gradually been revealed (23–25). Epigenetic modifications are not only crucial for the normal development and physiological functions of organisms but also closely related to the occurrence and development of various diseases, including cancer, neurodegenerative diseases and cardiovascular diseases (26–29). In recent years, advanced techniques such as high-throughput sequencing have propelled the rapid development of epigenetics (30), but challenges such as the complexity and cellular heterogeneity of epigenetics still remain to be addressed. In-depth studies of epigenetic mechanisms are of great significance for the prevention and treatment of diseases.

Previous studies have demonstrated that epigenetic modifications serve pivotal roles in embryonic skin morphogenesis, wound repair and diverse pathophysiological processes, including inflammation, angiogenesis and fibrosis (31–33). DNA methylation may influence wound healing by regulating the expression of cell cycle-related genes, thereby affecting the proliferation and differentiation of skin cells (34). Notably, N⁶-methyladenosine (m⁶A) methylation modifications on the mRNAs of type XVII collagen, integrin β4 and integrin α6 exert crucial regulatory effects on epidermal cell regeneration (35). Pathological scarring, a common manifestation of aberrant wound healing, arises from a complex interplay of genetic factors, wound characteristics, individual variables and dysregulated inflammatory responses during healing (36). Notably, imbalances in collagen synthesis and degradation are central to scar formation, while genetic predispositions and epigenetic regulation also critically influence keloid development (37–39). Therefore, deciphering the intricate regulatory networks of wound healing and exploring novel therapeutic strategies, such as targeting histone methylation enzymes [such as Jumonji domain containing 3 (JMJD3) and SET domain bifurcated histone lysine methyltransferase 2 (Setdb2)], modulating RNA methylation [such as methylation by fat mass and obesity-associated protein (FTO) and recognition by YTH domain family (YTHDF) proteins] and regulating ncRNAs [such as (miRNA/miR)-19a/b, miR-20a and long non-coding RNA (lncRNA) growth arrest specific 5 (GAS5)], may offer promising avenues to enhance tissue regeneration and minimize scar formation.

2. Epigenetic mechanisms influencing wound healing

Epigenetics focuses on the investigation of inheritable modifications in gene expression that occur without changes to the DNA sequence, instead being mediated by processes such as DNA methylation, histone modification, regulation by ncRNAs and RNA modification (Fig. 1), which in turn affect translation, nucleocytoplasmic transport and alternative splicing (40–43).

Figure 1.

Main epigenetic modifications and their mechanism. Epigenetics studies heritable changes in gene expression and cellular phenotypes that occur independently of DNA sequence alterations. Key mechanisms include DNA methylation, histone modifications (such as methylation and acetylation), non-coding RNA functions (including competing endogenous RNAs), RNA modifications (affecting stability and degradation), and processes influencing translation efficiency, nucleocytoplasmic transport and alternative splicing. These mechanisms collectively shape dynamic epigenetic landscapes, influencing chromatin structure, transcriptional accessibility, and cellular identity and function in response to environmental cues.

Histone methylation

Histone methylation is a key epigenetic modification and has attracted attention across various fields, including biology, medicine and genetics (44,45). This modification alters the structure and function of chromatin by adding methyl groups to specific amino acid residues on histones (46,47), thereby regulating gene expression and influencing a wide range of biological processes, such as cell differentiation (48), development (49), metabolism and disease onset (50).

Histone methylation primarily occurs on lysine and arginine residues, with lysines being mono-, di- or trimethylated and arginines being mono- or dimethylated (51). The most common sites of histone methylation are the lysine residues in the tail of histone H3, particularly at positions H3K4, H3K9, H3K27 and H3K36 (52). The function of these histone methylation sites depends on both the specific amino acid residue and the degree of methylation. Histone methylation is regulated by various enzymes, including methyltransferases and demethylases (50). Methyltransferases, such as SET domain proteins, including SET domain-containing protein 7 (SETD7) and SETD8, and the polycomb repressive complex 2 [PRC2; comprising enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2), SUZ12 polycomb repressive complex 2 subunit and embryonic ectoderm development], catalyze methylation reactions, while members of the histone lysine demethylase (KDM) family (such as KDM1A and KDM6B) are responsible for demethylation (53). The coordinated action of these enzymes ensures the dynamic balance of histone methylation states, thereby finely regulating gene expression (49). For instance, gene activation is typically associated with histone H3 lysine 4 trimethylation (H3K4me3) and H3K36me3 (54,55), with SETD7 catalyzing H3K4me3 to facilitate the binding of transcription initiation complexes (56,57). By contrast, gene silencing is linked to trimethylation of lysine 27 on histone 3 (H3K27me3) and H3K9me3, with the PRC2 complex catalyzing H3K27me3 via EZH2 to repress gene expression (58). Additionally, histone methylation can alter the structure of chromatin, making it more compact or relaxed, thereby affecting the accessibility of genes (59). Histone methylation modifications can also regulate gene expression by recruiting specific ‘reader’ proteins (such as bromodomain proteins) that recognize and bind to methylated histone residues, thereby influencing the binding of transcription factors and RNA polymerase, and regulating gene transcription activity (60).

The role of histone methylation in various diseases has gradually come into focus. Abnormal histone methylation modifications are closely related to the development of cancer (61), neurodegenerative diseases (62) and cardiovascular diseases (63). Therefore, in-depth research into the molecular mechanisms of histone methylation not only helps understand the complexity of gene expression regulation but also provides novel targets and strategies for the diagnosis and treatment of related diseases.

Histone acetylation

Histone acetylation is a crucial epigenetic modification that regulates gene expression and chromatin structure by adding acetyl groups to the lysine residues of histones (64,65). First identified in the 1960s, it is one of the most extensively studied histone modifications (66). Histone acetylation is primarily catalyzed by histone acetyltransferases, which transfer acetyl groups from acetyl-CoA to lysine residues on histones, neutralizing the positive charge of histones, weakening their interaction with DNA and relaxing the chromatin structure to promote gene transcription (64,67–69). By contrast, histone deacetylases remove acetyl groups, tightening the chromatin structure and inhibiting gene expression (70–72). Histone acetylation serves a role in various biological processes, including gene transcription regulation (73), cell cycle control (74), DNA replication and repair (75), cell differentiation (76), and stress responses (77). For example, acetylation sites such as histone H3 lysine 9 acetylation (H3K9ac) and H3K14ac are often found in the enhancer and promoter regions of active genes. These regions are crucial for gene expression. Additionally, acetylation is also observed in genes that are being transcribed, although the exact roles of these modifications are still being studied (78). With the development of proteomics technology, scientists can now more comprehensively analyze the dynamic changes in histone acetylation modifications (79). For example, mass spectrometry can be used to identify and quantitatively analyze histone acetylation sites, while chromatin immunoprecipitation sequencing can reveal the distribution of histone acetylation on the genome (80). These technological advancements provide strong support for in-depth understanding of the regulatory mechanisms and biological functions of histone acetylation. In summary, as a dynamic and reversible epigenetic modification, histone acetylation serves a key role in gene expression regulation and various biological processes. The abnormal levels of histone acetylation in diseases offer a novel perspective and potential targets for the diagnosis and treatment of related diseases (81).

DNA methylation

DNA methylation is a crucial epigenetic regulatory mechanism that can alter gene expression patterns and chromatin structure without changing the DNA sequence (82). This modification primarily occurs at the C-5 position of cytosine, usually in the context of CpG dinucleotides (83). In mammals, ~75% of CpG sites are methylated in somatic cells (84), and this high methylation status serves a vital role in genomic stability (85), gene expression regulation (86), genomic imprinting (87), X-chromosome inactivation (88), embryonic development (89) and tumorigenesis (90). The process of DNA methylation is catalyzed by the DNA methyltransferase (DNMT) family, including DNMT1, DNMT3A and DNMT3B (82,91). DNMT1 mainly maintains methylation status, ensuring that methylation patterns are accurately transferred from the parent strand to the daughter strand during DNA replication (92). By contrast, DNMT3A and DNMT3B are responsible for de novo methylation, which involves adding methyl groups to new DNA sequences (93). Additionally, the dynamic balance of DNA methylation is also influenced by demethylases, such as the ten-eleven translocation family of enzymes, which oxidize 5-methylcytosine to 5-hydroxymethylcytosine, thereby promoting DNA demethylation (94,95). DNA methylation has diverse functions, with its role in gene silencing being particularly prominent. When CpG islands in gene promoter regions are highly methylated, transcription factors are hindered from binding, leading to gene expression silencing (96). Furthermore, methylated CpG sites can be recognized by methyl-CpG-binding proteins (such as methyl-CpG-binding domain proteins and methyl-CpG binding protein 2), which then recruit histone deacetylases and methyltransferases, resulting in chromatin compaction and further inhibition of gene expression (97). In the development and progression of diseases, abnormal changes in DNA methylation are particularly prominent. For example, hypermethylation of tumor suppressor gene promoters is a common early event in tumorigenesis (98). Additionally, DNA methylation is closely related to neuropsychiatric disorders (99,100), aging (101) and obesity (102). As research into DNA methylation deepens, its potential as a biomarker is gradually being explored (103), with the hope that it can serve an important role in the early diagnosis, prognosis assessment and personalized treatment of diseases.

ncRNA

ncRNA constitutes a large category of gene transcription products, accounting for ~98.5% of all transcriptional output (104). Once considered non-functional ‘junk’ sequences, the roles of ncRNAs in gene expression regulation (105), cell differentiation (106), development (107), immune response (108) and disease onset (109) have been gradually revealed with in-depth research. Based on their function, ncRNAs can be divided into two major categories: Housekeeping ncRNAs such as small nucleolar RNA, small nuclear RNA, transfer RNA and ribosomal RNA; and regulatory ncRNAs such as lncRNA, circular RNA, Piwi-interacting RNA, small interfering RNA (siRNA) and miRNA (110). In terms of regulatory molecular mechanisms, ncRNAs exert their effects through various means.

lncRNAs can interact with specific proteins to form complexes. For example, X-inactive specific transcript lncRNA recruits PRC2 to cause X-chromosome inactivation (111); it can also bind to DNA to regulate chromatin structure and gene transcription (112); and it can interact with other RNA molecules to regulate RNA stability and translation efficiency (113,114), including acting as a miRNA sponge to relieve its inhibition of target mRNA. Additionally, lncRNAs can regulate gene transcription by serving as a cofactor for transcription factors or by altering chromatin accessibility through chromatin remodeling (115).

miRNA regulates gene expression by binding to the 3′ untranslated region of mRNA, inhibiting its translation or promoting its degradation, thereby negatively regulating gene expression (116). miRNA processing is relatively complex, with precursor miRNA being cleaved by Drosha and DiGeorge critical region gene 8 enzymes in the nucleus to form mature miRNA, which then enters the cytoplasm and is further processed by TAR RNA binding protein and Dicer enzymes, ultimately binding to argonaute proteins to form an RNA-induced silencing complex and regulate gene expression through translation inhibition or mRNA degradation (117).

siRNAs, a class of 20–25 nucleotide small regulatory RNAs, mediate post-transcriptional gene silencing through either mRNA degradation or translational inhibition upon binding to target mRNAs (118).

Collectively, ncRNAs have transcended their initial perception as genomic ‘dark matter’ to emerge as central regulators of biological systems. Their multidimensional mechanisms, spanning epigenetic remodeling, RNA interactome modulation and translational control, redefine the pivotal role of RNA in cellular homeostasis and disease states.

RNA methylation modifications

RNA methylation represents a crucial post-transcriptional modification mechanism that dynamically regulates RNA metabolism and function through the reversible addition of methyl groups to RNA molecules, thereby modulating RNA stability, splicing, translation and degradation without altering the RNA sequence (119). m⁶A, the most prevalent internal modification in eukaryotic mRNA, occurs predominantly at the N⁶ position of adenosine and exhibits sequence-specific enrichment at RRACH motifs (120). The dynamic equilibrium of m⁶A is maintained by three classes of regulatory proteins: ‘Writers’ [such as the methyltransferase like 3/14 complex (METTL3/14 complex); catalyzing methyl group transfer], ‘erasers’ (such as FTO and AlkB homolog 5; mediating demethylation) and ‘readers’ (such as the YTHDF proteins; recognizing m⁶A sites to regulate RNA fate) (121,122).

Functionally, RNA methylation orchestrates critical biological processes, including embryonic development (123), cell differentiation (124), immune responses (125) and circadian rhythm regulation (126), by fine-tuning mRNA splicing, nucleocytoplasmic transport, translation efficiency and decay rates (127). A study has demonstrated that m⁶A modifications regulate spatiotemporal gene expression by altering RNA secondary structures or recruiting specific binding proteins (for example, YTHDF2-driven mRNA degradation) (128). Pathologically, aberrant RNA methylation is closely linked to diverse diseases, including tumorigenesis (for example, METTL3 upregulation in leukemia) (129), neurodegenerative disorders (for example, FTO dysregulation in Alzheimer's disease) (130) and metabolic dysfunctions (for example, aberrant m⁶A modification of adipogenesis-related mRNAs) (131). Notably, the dynamic nature of m⁶A positions it as a promising diagnostic biomarker and therapeutic target. For instance, a preclinical study is exploring inhibitors targeting methyltransferase complexes for cancer therapy (132).

Advancements in single-base-resolution sequencing technologies and chemical biology tools are progressively unraveling the spatiotemporal regulatory networks of RNA methylation and its central role in epitranscriptomics. These insights underscore the potential of RNA methylation in advancing precision medicine and therapeutic innovation (32,133,134).

Epigenetic modifications serve important roles in numerous physiological processes, and some of their roles in wound healing are shown in Table I.

Table I.

Types of epigenetic modifications and their roles in wound healing.

Authors, year	Epigenetic modification	Mechanism of action	Specific role in wound healing	(Refs.)
Luo et al, 2019	DNA methylation	Silences gene expression via CpG island methylation	Regulates the cell cycle, proliferation and differentiation of skin cells	(34)
Chen et al, 2020	Histone methylation	Adds methyl groups to histones	Modulates inflammation and fibroblast activation	(44)
Gujral et al, 2020	Histone acetylation	Adds acetyl groups to histones	Regulates cell proliferation, cell cycle control and gene transcription	(64)
Chauvier and Walter, 2024	Regulation by non-coding RNA	miRNA and lncRNA binding to mRNA or chromatin	Regulates cell proliferation, collagen deposition and scar formation	(105)
Zhou et al, 2020	RNA methylation	m6A modifications	Regulates autophagy and fibrosis	(119)

lncRNA, long non-coding RNA; m⁶A, N⁶-methyladenosine; miRNA, microRNA.

3. Phases of wound healing

Wound healing is a complex and orderly physiological process involving interactions among various cell types, cytokines and growth factors. Wound healing is typically divided into four phases: Hemostasis, inflammation, proliferation and remodeling. Each phase has distinct pathophysiological characteristics, with sequential stages working synergistically to promote wound repair (8).

Hemostasis phase

The hemostasis phase is the initial stage of wound healing, usually completed within minutes to hours after injury. Its primary goals are rapid bleeding control, prevention of further blood loss and establishment a stable environment for subsequent repair (135). Upon injury, vascular smooth muscles contract immediately, narrowing blood vessels to reduce blood flow. This vasoconstriction, mediated by locally released neurotransmitters and vasoactive substances (such as catecholamines), constitutes the first step of hemostasis. Subsequently, platelets rapidly aggregate at the wound site, binding to exposed collagen to form a platelet plug (136). Activated platelets release growth factors such as platelet-derived growth factor and TGF-β, which not only facilitate coagulation but also provide signaling cues for inflammatory cell recruitment and tissue repair (137). Concurrently, coagulation factors are activated to form a fibrin clot, reinforcing hemostasis (138). Ultimately, a blood clot forms a protective scab, preventing further bleeding and infection (138). However, coagulation disorders (such as hemophilia) may impair platelet aggregation or clotting factor function, leading to persistent bleeding and delayed healing (139).

Inflammation phase

The inflammation phase typically lasts days to a week. Its primary objectives are pathogen clearance, removal of necrotic tissue and creation of a clean microenvironment for repair (140). Neutrophils and macrophages rapidly migrate to the wound site (141). Neutrophils release myeloperoxidase and elastase to form neutrophil extracellular traps for pathogen entrapment and killing (142). Macrophages phagocytose pathogens and debris while releasing cytokines (such as IL-1β and TNF-α) and growth factors (such as fibroblast growth factor and VEGF) to regulate inflammation and stimulate fibroblast activity (143). Localized redness, swelling, pain and heat reflect vascular dilation, increased blood flow and inflammatory mediator activity (144). However, excessive inflammation (for example, in diabetic wounds) may lead to chronic non-healing due to prolonged cytokine upregulation and impaired tissue repair (145).

Proliferation phase

The proliferation phase spans weeks to months, focusing on tissue reconstruction through cell proliferation and migration (146). Fibroblasts proliferate and synthesize ECM components such as collagen to fill the wound defect (147). Chemotactic signals guide fibroblast migration, while angiogenesis, stimulated by angiopoietins and VEGF, generates new capillaries to supply oxygen and nutrients (148). Granulation tissue, composed of new vessels and collagen, forms the foundation for re-epithelialization (149). Keratinocytes at the wound edge proliferate and migrate under growth factor stimulation to restore the epidermal barrier (150,151). Delayed healing may occur in diabetes or aging due to impaired fibroblast/endothelial cell function, while excessive collagen deposition can lead to keloid formation (152).

Remodeling phase

The remodeling phase may last several months to years, aiming to optimize tissue structure and function (8). Collagen III is gradually replaced by stronger collagen I, balancing synthesis and degradation to enhance tissue integrity (153). Transient cells (such as macrophages and fibroblasts) undergo apoptosis, reducing inflammation (154). Wound strength improves as excess collagen is remodeled, restoring mechanical properties (155). Abnormal remodeling may result in scar contracture or hypertrophy. For instance, keloid formation stems from hyperactive fibroblasts and excessive collagen deposition (156).

Summary

The four phases of wound healing are interdependent, with physiological processes in each stage being critical for successful repair (8). Pathological disruptions (such as impaired coagulation, chronic inflammation or aberrant remodeling) may lead to healing failure (157–160). Understanding these pathophysiological mechanisms enables targeted therapeutic strategies, such as anti-inflammatory interventions for chronic wounds, pro-angiogenic agents to accelerate proliferation and collagen modulation to improve scar outcomes. In-depth research into these stages and their regulatory mechanisms holds promise for advancing wound care efficacy. Table II summarizes the four phases of wound healing and the characteristics of each phase.

Table II.

Phases of wound healing and their characteristics.

Authors, year	Phase	Time frame	Key features	Key cell types	(Refs.)
Guo et al, 2021	Hemostasis	Minutes to hours	Vasoconstriction, platelet aggregation, coagulation	Vascular smooth muscle cells, platelets	(135)
Eming et al, 2017	Inflammation week	Days to a of necrotic tissue, inflammatory cell infiltration	Pathogen clearance, removal	Neutrophils, macrophages	(140)
Landén et al, 2016	Proliferation	Weeks to months	Tissue reconstruction, cell proliferation and migration, ECM deposition	Fibroblasts, endothelial cells, keratinocytes	(146)
Singh et al, 2023	Remodeling	Months to years	Tissue structure, collagen optimization	Fibroblasts, macrophages remodeling, scar contraction	(153)

ECM, extracellular matrix.

4. Epigenetic modifications in wound healing

Epigenetic modifications serve roles in each phase of wound healing. Some of the research progress in this field is summarized subsequently. Table III summarizes a selection of representative findings.

Table III.

Key epigenetic regulators and their mechanisms.

Authors, year	Regulator	Mechanism of action	Specific role in wound healing	(Refs.)
Audu et al, 2022;	JMJD3	Regulates inflammatory genes via	Enhances inflammatory	(177–181)
Ariel, 2023;		H3K27me3	response in diabetic wounds
Jiang et al, 2021;
Zhang et al, 2019;
Nakka et al, 2022
Kimball et al, 2019	Setdb2	Modulates macrophage phenotype shift	Targeting of Setdb2 improves diabetic wound healing	(182)
Dong et al, 2025	FTO	Regulates TRIB3 expression via m6A modification	Promotes diabetic wound healing	(185)
Li et al, 2021	miR-19a-3p	Targets tissue factor to inhibit coagulation	Potential therapeutic target for sepsis-induced DIC	(188)
Li et al, 2023	H19-EZH2 interaction	Regulates H3K27me3 modifications	Promotes liver fibrosis; potential antifibrotic therapeutic target	(201)

DIC, disseminated intravascular coagulation; EZH2, enhancer of zeste 2 polycomb repressive complex 2 subunit; FTO, fat mass and obesity-associated protein; H3K27me3, trimethylation of lysine 27 on histone 3; JMJD3, Jumonji domain containing 3; m⁶A, N⁶-methyladenosine; miR, microRNA; Setdb2, SET domain bifurcated histone lysine methyltransferase 2; TRIB3, Tribbles pseudokinase 3.

Regulation of epigenetic modifications in the hemostasis phase

The hemostasis stage is the initial stage of wound healing (initiated immediately after injury), characterized by rapid closure of blood vessels, rapid coagulation and release of various factors, paving the way for the subsequent inflammation phase (146). If the hemostatic response is either insufficient or excessive, or if the coagulation mechanism is abnormal, it will directly affect the healing process (161).

Abnormalities in coagulation function can delay wound healing. A variety of factors can influence the coagulation process in the body, including epigenetic modifications (162). Platelets produced by megakaryocytes serve an indispensable role in key physiological functions such as hemostasis, coagulation and immune regulation (163). The transcription factors friend leukemia virus integration 1 (Fli-1) and GATA binding protein 1 (GATA-1) are crucial for the development of megakaryocytes. Studies have confirmed that the transcriptional activity of the GATA-1 and Fli-1 genes is closely related to the acetylation of histone H3 and the phosphorylation of RNA polymerase II in their promoter regions. The acetylation of histone H3 and the phosphorylation of RNA polymerase II are important regulatory mechanisms for the function of transcription factors (164–166). In addition, another study has experimentally demonstrated that the DNA methylation level of the platelet endothelial aggregation receptor 1 (PEAR1) gene is negatively associated with the number of platelet-monocyte conjugates, indicating that DNA methylation may regulate platelet function and interactions by affecting gene expression (167). In the field of clinical research, a study on neonates with sepsis-induced disseminated intravascular coagulation (DIC) found that, compared with those of the healthy control group, the expression levels of miR-19a-3p in these infants were reduced, while the expression levels of tissue factor (TF) were increased (168). This finding suggests that miR-19a-3p may serve an important regulatory role in the occurrence and development of DIC. Further cell experiments have revealed that overexpression of miR-19a-3p could reduce the mRNA and protein expression levels of TF, as well as the ratios of phosphorylated (p-)AKT/AKT, p-ERK/ERK, p-P65/P65 and p-IκB-α/IκB-α, and decreased the procoagulant activity of TF (168,169). These results indicate that miR-19a-3p regulates TF through multiple signaling pathways. Studies have also found that the regulatory effect of miR-19a-3p on TF depends on the activity of the NF-κB and AKT signaling pathways, providing key clues for understanding the mechanism of action of miR-19a-3p in DIC (168,170). Therefore, miR-19a-3p may inhibit the occurrence of DIC by targeting TF and holds promise as a potential therapeutic target for the treatment of sepsis-induced DIC (171).

The hemostasis stage is crucial for initiating wound healing, and abnormalities in the coagulation function can impact this process. Epigenetic changes serve as critical regulators of platelet function and interactions, thus offering a promising therapeutic target.

Regulation of epigenetic modifications in the inflammation phase

The inflammatory stage of wound healing serves a crucial role, such as eliminating pathogens and necrotic tissues, preventing the spread of infection, and supporting subsequent tissue repair (172). It also releases key signaling molecules to activate fibroblasts and vascular endothelial cells, promoting granulation tissue formation and angiogenesis (173). If the inflammatory response is too strong or too weak, or lasts too long, this can lead to abnormal healing. Insufficient or defective inflammation can cause the spread of infection and even sepsis, ultimately resulting in delayed healing (174,175). An excessive inflammatory response or chronic inflammation can damage new tissues and release excessive fibrotic factors, leading to scar tissue formation or tissue fibrosis (176).

A study involving single-cell RNA sequencing has revealed that the levels of JMJD3 in macrophages of diabetic wounds were elevated compared with those in macrophages of healthy individuals, leading to increased expression of inflammatory genes (177). The increase in JMJD3 induced the transcription of inflammatory genes in wound macrophages via an H3K27me3 mechanism (178). These studies have revealed the mechanism by which JMJD3 regulates inflammatory responses through the Janus kinase (JAK)1/3-STAT3 signaling pathway, and have found that the stimulator of interferon genes (STING) gene is regulated by JMJD3 (178–181). In the diabetic state, STING limits wound repair and enhances inflammation (177). In addition, another study has shown that JMJD3 can drive hyaluronic acid synthesis to serve a pro-regenerative role (181). The histone methyltransferase Setdb2 serves a crucial role in macrophage plasticity, regulating the transition of macrophages from an inflammatory phenotype to a reparative one. This process is impeded in diabetic wounds due to impairment of the IFNβ-Setdb2 axis, resulting in a persistent inflammatory state of macrophages. Targeting Setdb2 by specific knockout can improve diabetic wound healing and holds potential therapeutic value (182). IFN-κ is upregulated in keratinocytes early after injury and is essential for tissue repair; however, its expression is decreased in diabetic conditions, leading to impaired early inflammation (183). A study has reported that the histone methyltransferase mixed-lineage leukemia 1 (MLL1) regulates IFN-κ expression via an H3K4me3 mechanism, and MLL1 expression is reduced in keratinocytes of patients with type 2 diabetes compared with keratinocytes of healthy individuals (184). Administration of IFN-κ early after injury can improve diabetic wound repair (184). FTO promotes autophagy in keratinocytes by regulating the m⁶A modification of Tribbles pseudokinase 3, thereby accelerating diabetic wound healing, providing novel insights for the development of m⁶A-targeted therapies for refractory diabetic wounds (185). The m⁶A reader YTH N⁶-methyladenosine RNA binding protein C1 regulates autophagic flux by modulating the stability of nuclear sequestosome 1 mRNA in diabetic keratinocytes, thereby influencing wound healing (186). Inflammation is a factor contributing to the changes in plasma miRNA concentrations in patients with non-healing wounds, where miR-191 regulates cell migration and angiogenesis by targeting zonula occludens-1, thereby delaying the tissue repair process (187). A study has revealed the crucial role of miR-19a/b and miR-20a in modulating wound inflammation, with their deficiency potentially leading to persistent inflammation and impaired healing in chronic wounds. However, the combined application of these two miRNAs could improve wound healing in a mouse model of type 2 diabetes (188). Diabetic ulcer formation is driven by chronic hyperglycemia, which induces tissue damage via interconnected pathways such as microvascular and neuropathic impairments, chronic inflammation, neurovascular injury, impaired immune function and biofilm formation, creating a difficult-to-treat pathological microenvironment (189,190), as shown in Fig. 2. Table IV summarize the factors, such as JMJD3 and Setdb2, in diabetic wounds and their impacts and mechanisms. miR-221-3p inhibits high-glucose-induced inflammatory responses by targeting dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) and promotes wound healing via the DYRK1A/STAT3 signaling pathway, providing a potential therapeutic target for the treatment of diabetic foot ulcers (191). The expression levels of lncRNA GAS5 are upregulated in diabetic wounds, and its high expression is associated with the prolonged presence of proinflammatory (M1) macrophages. Inhibiting GAS5 expression can promote diabetic wound healing by facilitating the transition of M1 macrophages to M2 macrophages, making GAS5 a potential therapeutic target to improve diabetic wound healing (192).

Figure 2.

Pathological mechanisms underlying diabetic ulcer formation. Chronic hyperglycemia drives a self-perpetuating cycle of tissue damage through several interconnected pathways: i) Sustained hyperglycemia induces microvascular and neuropathic impairments, leading to neurovascular injury; ii) chronic inflammation, dysregulated epigenetically, exacerbates tissue damage; iii) neurovascular injury compromises perfusion and sensory feedback; iv) decreased immune function impairs macrophage polarization and neutrophil extracellular trap formation, facilitating persistent infections; and v) persistent infections are promoted by biofilm formation in immunocompromised tissue. Collectively, these processes establish a pathological microenvironment resistant to standard therapies, contributing to the 15–25% lifetime amputation risk in diabetic patients.

Table IV.

Key epigenetic regulators in diabetic wounds.

Authors, year	Factor in diabetic wounds	Changes	Impact	Mechanism	(Refs.)
Audu et al, 2022;	JMJD3	Elevated levels	Increased inflammation	Regulates inflammatory gene	(177–181)
Ariel, 2023;				expression via H3K27me3
Jiang et al, 2021;
Zhang et al, 2019;
Nakka et al, 2022
Li et al, 2021	miR-19a/b, miR-20a	Reduced expression	Impaired inflammatory response and cell migration	Modulate inflammation and cell migration genes	(188)
Kashiyama et al, 2012	miR-196a	Downregulated expression	Exacerbated scar formation	Regulates collagen synthesis-related genes	(213)
Dong et al, 2025;	FTO, YTHDC1	Abnormal m6A	Impaired autophagy and	Regulate RNA stability and	(185,186)
Liang et al, 2022		regulation	fibrosis	translation efficiency via m6A modifications

FTO, fat mass and obesity-associated protein; H3K27me3, trimethylation of lysine 27 on histone 3; JMJD3, Jumonji domain containing 3; m⁶A, N⁶-methyladenosine; miR, microRNA; YTHDC1, YTH N⁶-methyladenosine RNA binding protein C1.

The inflammatory stage of wound healing is essential to eliminate pathogens, prevent infection spread and support tissue repair; however, abnormal inflammatory responses can lead to delayed or impaired healing (172). Previous studies have identified key epigenetic regulators which serve critical roles in modulating inflammation and promoting diabetic wound healing through various signaling pathways and mechanisms (193–195). These findings provide valuable insights and potential therapeutic targets to improve wound repair in diabetic and chronic non-healing wounds.

Regulation of epigenetic modifications in the proliferation phase

During the proliferative phase of wound healing, fibroblasts proliferate and secrete ECM to form granulation tissue, which provides support for the wound (146). Endothelial cells proliferate and migrate to form new blood vessels, supplying nutrients to the wound. In addition, keratinocytes proliferate and migrate to cover the wound, restoring the skin barrier function (196,197). However, if the proliferative phase is abnormal, it can have adverse effects on wound healing. Insufficient proliferation can lead to delayed wound healing and increased risk of infection, while excessive proliferation may cause scar formation and tissue fibrosis, affecting function and appearance, and even resulting in chronic wounds (198).

A study has shown that valproic acid controlled myofibroblast activation, proliferation and production of ECM proteins in myofibroblasts by regulating the acetylation level of histone H3 (199). Additionally, miRNAs serve a role in regulating the composition of the ECM and cell phenotype. miRNAs, such as miR-125a/b and miR-146a, influence the formation and remodeling of the ECM by regulating the synthesis and turnover of key ECM molecules and their receptors, as well as by affecting the abundance of cytokines and growth factors (200). Changes in miR-125a/b and miR-146a expression can lead to pathological consequences, such as the formation of scar tissue (200). EZH2, an epigenetic regulator that catalyzes H3K27me3, can be bound by the lncRNA H19, which modulates its epigenetic modifications. This interaction promotes the activation and proliferation of hepatic stellate cells, thereby driving the development of fibrosis in the liver. Targeting the H19-EZH2 interaction holds promise as a novel therapeutic target for fibrosis (201). A previous study has revealed the novel roles of non-coding double-stranded RNA as a damage-associated molecular pattern and the antimicrobial peptide LL-37 in skin wound repair. They promote wound healing by regulating the expression of various growth factors and underscore the intricate molecular interactions within the wound environment (202). SETD2 is the only known histone H3K36 tri-methylase. By establishing an epidermis-specific Setd2-knockout mouse model, a previous study has revealed that the absence of SETD2 could accelerate re-epithelialization during skin wound healing by promoting the proliferation and migration of keratinocytes through the activation of the AKT/mTOR signaling pathway (203). miR-126 is highly expressed in burn wound tissues and HUVECs exposed to heat stress, while the expression levels of HOX antisense intergenic RNA (HOTAIR) and Sciellin are downregulated after thermal injury. HOTAIR and Sciellin can competitively bind to miR-126, functioning as competitive endogenous RNAs. miR-126 promotes the proliferation, migration and angiogenesis of endothelial cells while inhibiting apoptosis, whereas HOTAIR and Sciellin exert opposite effects in HUVECs. The mechanism by which the HOTAIR/miR-126/Sciellin axis promotes burn wound healing through the regulation of angiogenesis indicates that miR-126 serves a role in burn wound healing by interacting with HOTAIR and Sciellin (204).

The proliferative phase of wound healing can support wound closure and tissue repair (205). However, abnormal proliferation can lead to delayed healing, scar formation or chronic wounds (172). Previous studies have highlighted the regulatory roles of epigenetic modifications in controlling ECM remodeling, cell proliferation, fibrosis development and angiogenesis (206–209). These findings underscore the complex molecular mechanisms driving the proliferative phase and offer potential therapeutic targets for improving wound healing outcomes.

Regulation of epigenetic modifications in the remodeling phase

The remodeling phase of wound healing is a crucial period for repairing damaged tissues, primarily optimizing tissue structure and enhancing its function. During this phase, collagen fibers are reorganized, tissue strength and elasticity are gradually restored, and the wound also contracts and stabilizes (8). Dysfunction in this phase may lead to tissue fibrosis, excessive scar proliferation or chronic non-healing wounds, affecting appearance and function, and potentially causing complications such as infection (210).

lncRNAs serve a key role in skin scarring and subsequent scar carcinogenesis (39,211). In keloid tissues and human kidney fibroblasts, the expression levels of GNAS antisense RNA 1 (GNAS-AS1) and runt-related transcription factor 2 (RUNX2) are elevated, whereas miR-188-5p expression is reduced, compared with those in normal tissue. GNAS-AS1 modulates the miR-188-5p/RUNX2 signaling axis to influence keloid cell proliferation, migration and invasion, making it a potential target to prevent and treat keloids (211). HOXA11 antisense RNA (HOXA11-AS) promotes the formation and growth of keloids by regulating the miR-182-5p/zinc finger protein 217 axis. Inhibiting HOXA11-AS expression may become a novel strategy for preventing keloid formation (212). The downregulation of miR-196a in keloid fibroblasts leads to excessive collagen deposition, which may promote the formation of keloids or scar (213). Additionally, during the wound healing and remodeling phase, RNA epigenetic modifications may malfunction. Studies have found that fibroblasts in keloids exhibited high levels of m⁶A modification, and the hypermethylation of the Wnt/β-catenin signaling pathway may promote the formation of keloids (214,215). Development of drugs that can inhibit this modification may become a novel strategy to prevent keloid formation (38).

The remodeling phase of wound healing is vital for tissue repair and functional enhancement, with collagen reorganization and wound stabilization occurring. Dysregulation in this phase can lead to complications such as tissue fibrosis and chronic wounds (216). Epigenetic modifications serve abnormal roles in wound healing, suggesting that they may serve as potential therapeutic targets for preventing keloid formation.

Diabetic wounds are complex pathological conditions marked by slow healing, high susceptibility to infection and difficulty in recovery. These issues arise from long-term hyperglycemia, which leads to microvascular and neuropathic changes, as well as compromised immune function in diabetic patients (152,217,218).

5. Conclusion

The present review provides a comprehensive exploration of the role of epigenetic modifications in wound healing and their potential therapeutic applications. Wound healing is a complex physiological process that involves the coordinated action of various cell types and molecular mechanisms, with epigenetic modifications serving a crucial regulatory role. Research has shown that epigenetic modifications, including DNA methylation, histone modifications, regulation by ncRNAs and RNA methylation, influence the speed and quality of wound healing by regulating gene expression, cell function and intercellular signaling. For example, DNA methylation affects the hemostasis phase by regulating genes related to platelet function (such as PEAR1), histone methyltransferases JMJD3 and Setdb2 participate in the chronic inflammation of diabetic wounds by modulating inflammation-related pathways (such as the JAK/STAT pathway), ncRNAs (such as GNAS-AS1) regulate cell proliferation and collagen deposition by targeting signaling molecules, and m⁶A modifications influence autophagy and fibrosis through the binding and recognition of m⁶A modifications by YTHDF family proteins. These findings provide a theoretical basis for therapeutic strategies targeting epigenetic mechanisms, such as small molecule inhibitors and RNA therapies.

There are still some limitations in the current research. First, most mechanistic studies are based on animal models or in vitro cell experiments. Additional validation of the safety and efficacy of these therapeutic strategies targeting epigenetic mechanisms is required before they can be translated into clinical use. Second, the complexity of the epigenetic regulatory network means that interventions targeting a single site may cause off-target effects, and more precise regulatory tools need to be developed. In addition, the heterogeneity of the wound microenvironment (such as subpopulations of immune cells and fibroblasts) and its impact on epigenetic interventions have not been fully elucidated, and single-cell multi-omics technologies need to be used to gain a deeper understanding. For example, the cell-specific and spatiotemporal regulatory mechanisms of epigenetic modifications have not been fully elucidated, especially their dynamic changes in complex wound environments. Furthermore, the interactions between different epigenetic modifications and how they collectively influence the wound healing process requires further investigation.

Epigenetic modification-targeted therapies represent a significant frontier in precision medicine, yet their path to clinical translation is fraught with challenges. The catalytic domains of numerous epigenetic modifying enzymes are highly conserved among family members, making the design of highly selective inhibitors difficult. Concurrently, the epigenetic state itself is highly dynamic and reversible (219). Consequently, the therapeutic effects may not be sustained, necessitating long-term or repeated dosing, which increases the risk of drug resistance and toxicity (220). Furthermore, assessing epigenetic states, such as the methylation levels of specific genes or histone modification profiles, imposes stringent tissue sampling requirements (typically requiring fresh tissue), and their detection in bodily fluids (such as blood) is challenging and offers limited representation (221–223). The absence of definitive biomarkers hinders the precise identification of patient populations most likely to benefit from specific epigenetic modification-targeted therapies. Collectively, these difficulties contribute to the current lack of clinical trial evidence supporting epigenetic interventions for wound healing.

Epigenetic modifications hold great potential for improving wound healing. With the development of high-throughput technologies such as single-cell RNA sequencing and spatial transcriptomics, researchers are able to analyze the dynamic changes and molecular mechanisms of cells in the wound healing process at a higher resolution. For instance, a recent study has used these technologies to construct a spatiotemporal cell atlas of human skin wound healing, revealing the roles of different cell types and molecules in trauma repair (224). In addition, the continuous progress of epigenetic editing technologies also provides possibilities for developing novel wound healing strategies based on epigenetic modifications. For example, epigenetic editing technologies that achieve gene silencing by modifying the chemical structure around DNA have been demonstrated to have potential applications in treating hypercholesterolemia and related cardiovascular diseases (225).

Future research may focus on the specific mechanisms of epigenetic modifications in different wound types and pathological states, as well as exploring their potential as therapeutic targets, and their safety and efficacy. In particular, research on the cell-specific and spatiotemporal regulatory mechanisms of epigenetic modifications will help develop more precise therapeutic strategies to promote wound healing, reduce scar formation and prevent the occurrence of chronic wounds. Furthermore, further investigation into the interactions between different epigenetic modifications and how they collectively influence the wound healing process will also provide a theoretical basis for developing combination therapies. In summary, research on epigenetic modifications in wound healing not only helps to deepen the understanding of their complex regulatory mechanisms but also provides a wide range of possibilities for creating novel treatment methods.

Funding Statement

Funding: No funding was received.

Availability of data and materials

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Authors' contributions

JC was involved in conceptualization and project administration, provided resources, supervised the study, wrote the original draft, and reviewed and edited the manuscript. WQ was involved in conceptualization and project administration, provided resources, supervised the study, wrote the original draft, and reviewed and edited the manuscript. FC was involved in conceptualization and project administration. XL was involved in conceptualization, project administration, provided resources, and reviewed and edited the manuscript. MF was involved in conceptualization and project administration. WC wrote the original draft. YZ was involved in project administration, provided resources, supervised the study, wrote the original draft, and reviewed and edited the manuscript. Data authentication is not applicable. All authors have read and approved the final version of the manuscript.

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Competing interests

The authors declare that they have no competing interests.