Decapping scavenger enzyme as a promising biomarker in diabetic foot ulcers: A need for cautious interpretation

Abstract

Diabetic foot ulcer (DFU) remains a major cause of morbidity and lower-limb amputation worldwide. Accurate risk assessment and timely intervention are critical for improving healing outcomes. A recent study identified the decapping scavenger enzyme (DCPS), an N7-methylguanosine (m7G)-related gene, as a potential diagnostic and therapeutic biomarker for DFU. Reduced DCPS expression was found to impair keratinocyte proliferation, migration, and cell-cycle progression, highlighting its possible role in m7G-mediated wound repair. Despite these promising insights, several challenges must be addressed before DCPS can be translated into clinical practice. First, DCPS expression may vary among patients with metabolic or inflammatory disorders, limiting its disease specificity. Second, standardized reference ranges for DCPS quantification have not yet been established. Moreover, whether DCPS modulation can directly enhance wound healing remains uncertain. Overall, DCPS provides a novel mechanistic link between RNA methylation and chronic wound pathology, but its clinical application as a biomarker or therapeutic target warrants careful validation.

Key Words: Diabetic foot ulcer; Decapping scavenger enzyme; RNA methylation; Biomarker; Keratinocyte proliferation; Wound healing

Core Tip: Decapping scavenger enzyme (DCPS), an N7-methylguanosine-related gene, has emerged as a potential diagnostic and therapeutic biomarker for diabetic foot ulcer (DFU) by linking RNA methylation to impaired keratinocyte function and wound repair. However, its variable expression, lack of standardized reference ranges, and uncertain therapeutic efficacy necessitate further validation. Future research should clarify DCPS’s regulatory mechanisms, develop clinical quantification standards, and assess targeted modulation to enhance its diagnostic precision and therapeutic potential in DFU.

TO THE EDITOR

Diabetic foot ulcer (DFU) remains a major global cause of morbidity and lower-limb amputation, affecting approximately 15%-25% of individuals with diabetes[1,2]. Despite advances in wound care, glycemic control, and comprehensive management strategies in recent years, DFU is still characterized by delayed healing, high recurrence rates, and a substantial risk of severe complications, imposing a significant burden on patients’ quality of life and on healthcare systems[3,4]. The 5-year mortality rate for DFU patients is approximately 30%, rising to over 70% in cases requiring major amputation[5]. Therefore, accurate risk assessment, early diagnosis, and timely intervention are critical for improving healing outcomes and reducing amputation risk in patients with DFU.

The decapping scavenger enzyme (DCPS), an N7-methylguanosine (m7G)-related gene, has recently attracted considerable attention. DCPS plays a critical role in mRNA metabolism by catalyzing the hydrolysis of the 5’cap structure, thereby regulating mRNA degradation, nucleotide recycling, and translational control[6-10]. Recent research by Xiao et al[11] has highlighted DCPS as a pivotal regulator in the pathogenesis of DFU, with potential as both a diagnostic and therapeutic biomarker. Downregulation of DCPS was shown to significantly inhibit keratinocyte proliferation and migration, while perturbing cell-cycle progression, indicating its central role in m7G-mediated wound repair. These findings uncover a novel mechanistic link between RNA methylation and chronic wound pathology, providing critical molecular insights into the impaired healing processes characteristic of diabetic chronic wounds.

Despite its demonstrated biological potential, the clinical translation of DCPS faces several challenges. First, DCPS expression may vary among individuals due to differences in metabolic or inflammatory status, which limits its reliability as a disease-specific biomarker[12-14]. Second, standardized detection methods and reference ranges for DCPS are currently lacking, introducing uncertainty in clinical measurement and interpretation. Moreover, it remains unclear whether direct modulation of DCPS can significantly enhance wound healing, these issues are summarized in Figure 1. This letter provides a critical evaluation of DCPS as a biomarker and therapeutic target in DFU. While DCPS shows promise, its application as a clinical diagnostic or interventional tool requires cautious validation, and further research is needed to advance its translation from basic research to clinical practice.

Figure 1 Overview of the diagnostic and therapeutic potential of decapping scavenger enzyme in diabetic foot ulcer and the associated clinical challenges. Decapping scavenger enzyme (DCPS), a key regulator in N7-methylguanosine RNA metabolism, has emerged as a promising biomarker and therapeutic target for diabetic foot ulcer (DFU). Reduced DCPS expression impairs keratinocyte proliferation, migration, and cell-cycle progression, directly linking RNA methylation to dysfunctional wound repair. However, the clinical translation of DCPS faces significant hurdles, including limited disease specificity due to variable expression in patients with metabolic or inflammatory comorbidities, a lack of standardized detection methods and reference ranges for reliable quantification, and uncertain in vivo therapeutic efficacy of DCPS modulation. This figure highlights the necessity of developing multi-faceted strategies that integrate DCPS with other clinical parameters and molecular biomarkers to enhance diagnostic accuracy and therapeutic potential. Future research must focus on establishing standardized assays, elucidating DCPS regulatory mechanisms, and validating targeted interventions through robust preclinical and clinical studies to advance its application in personalized DFU management. DCPS: Decapping scavenger enzyme; m7G: N7-methylguanosine. Created in BioRender (Supplementary material).

The role of DCPS in wound healing

DCPS is a critical terminal enzyme in mRNA cap metabolism, catalyzing the hydrolysis of m7G cap structures to complete cap removal and prevent the abnormal accumulation of cap analogs within cells. This terminal decapping reaction plays an essential role in maintaining mRNA stability, nucleotide recycling, and cap-dependent post-transcriptional gene regulation[7,15,16]. Structural and enzymatic studies have demonstrated that DCPS functions synergistically with complexes such as Xrn1 and Dcp1/Dcp2 in eukaryotic mRNA degradation pathways, collectively sustaining mRNA homeostasis[17,18]. At the molecular level, DCPS regulates the availability of cap-binding proteins, such as eIF4E, by removing cap remnants generated from mRNA decay, thereby indirectly influencing critical processes including translation initiation, mRNA export, and pre-mRNA splicing[19,20]. In addition, DCPS interacts with nuclear pre-mRNA processing complexes, including the cap-binding complex and the survival motor neuron complex, contributing to nuclear mRNA maturation and export[21-23]. Evidence further implicates DCPS in the miRNA metabolic cycle, modulating precursor miRNA splicing and turnover, suggesting a broader role in post-transcriptional regulatory networks[18]. Therefore, DCPS functions not only as the terminator of mRNA decay but also as a key gatekeeper of post-transcriptional gene regulatory balance.

The m7G modification represents one of the most critical post-transcriptional epitranscriptomic marks in eukaryotic cells. It is widely present at the 5′ end and internal sites of mRNA, rRNA, and tRNA. This chemical modification stabilizes RNA secondary structures, enhances ribosomal recognition, and promotes translational efficiency, thus serving as a fundamental determinant of cellular proteostasis[24]. Increasing evidence demonstrates that aberrant m7G modification can lead to defective protein synthesis, impaired cell cycle progression, altered cellular migration, and dysregulated responses to cellular stress[25-27]. These observations underscore the critical importance of precise RNA cap regulation in maintaining normal cellular function and tissue integrity. In the pathological context of DFU, chronic hyperglycemia induces oxidative stress, persistent inflammation, and widespread cellular dysfunction, collectively impairing cutaneous regeneration[28]. Keratinocytes, the principal epithelial cells in the skin, play a central role in re-epithelialization, angiogenesis, and extracellular matrix (ECM) remodeling, with their proliferative and migratory capacity largely determining the speed and quality of wound closure. Fibroblasts and endothelial cells contribute to ECM deposition and neovascularization, while immune cells, including macrophages and T lymphocytes, orchestrate the resolution of inflammation and reparative signaling. Any disruption in the temporal coordination of these cellular events can result in stalled healing and the development of chronic, non-healing wounds[29,30].

Experimental studies have shown that DCPS expression is markedly downregulated in DFU lesions, particularly within the epidermal layer. Weighted gene co-expression network analysis combined with receiver operating characteristic curve assessment suggests that DCPS may serve as a potential diagnostic and prognostic biomarker. In vitro, knockdown of DCPS in normal human epidermal keratinocytes under diabetic conditions induces cell cycle arrest, impairs proliferation and migration, and increases apoptosis[11]. Mechanistic analysis has revealed that DCPS silencing downregulates the expression of key cell cycle proteins, including cyclin D1 and CDK6. These findings indicate that DCPS regulates keratinocyte activity through m7G-mediated RNA metabolism, thereby influencing wound re-epithelialization[11]. Mechanistically, DCPS deficiency may impede wound healing through multiple interconnected pathways. The accumulation of cap degradation products can competitively bind eIF4E, reducing its availability for normal mRNAs and thereby decreasing the translation efficiency of transcripts critical for tissue repair[11,31]. In addition, aberrant mRNA degradation may disrupt the dynamic expression of repair-associated factors, including EGF, KGF, TGF-β, and MMP-TIMP systems, leading to impaired epithelial-stromal crosstalk[32-34]. DCPS-mediated abnormalities in miRNA and lncRNA metabolism may further interfere with inflammation resolution and angiogenic signaling[17]. Collectively, these disruptions prolong inflammatory responses, compromise neovascularization, and delay tissue remodeling, ultimately leading to chronic non-healing wounds.

Given that effective wound repair depends on precise protein synthesis and tightly regulated post-transcriptional control, DCPS establishes a novel molecular link between RNA methylation and tissue regeneration. By coordinating mRNA decay and translation fidelity, DCPS orchestrates multiple cellular processes at the epitranscriptomic level[15,19]. Thereby determining the regenerative capacity of diabetic wound tissues. Elucidating the molecular mechanisms underlying DCPS function not only enhances our understanding of DFU pathophysiology but also provides a promising framework for developing RNA metabolism-targeted therapeutic strategies aimed at restoring normal wound healing and improving clinical outcomes.

Challenges in using DNA methylation into clinical practice

Although the molecular mechanisms of DCPS in wound biology are gradually being elucidated, its clinical translation remains at an early stage and faces several critical challenges. These challenges include limited disease specificity, the lack of standardized reference ranges, and the currently unclear therapeutic potential.

Limited disease specificity: The expression of DCPS may exhibit considerable variability in patients with metabolic syndrome, chronic inflammation, or other systemic comorbidities, which could limit its specificity for DFU. Specifically, changes in DCPS levels may not solely reflect local wound pathology but may also be influenced by systemic metabolic status, persistent low-grade inflammation, or oxidative stress[35]. Factors such as glycemic fluctuations, lipid abnormalities, sustained elevation of inflammatory cytokines, and increased oxidative stress can systemically modulate DCPS expression, potentially obscuring its wound-specific signals[7,36]. This systemic influence may result in DCPS alterations observed in clinical samples being driven in part by the overall metabolic or immune environment rather than solely by the wound healing process. Consequently, relying exclusively on DCPS expression to assess wound status may underestimate or overestimate the regenerative capacity of the tissue, thereby affecting its accuracy as a biomarker.

To enhance the reliability of DCPS for DFU diagnosis and prognosis, it may be necessary to integrate its measurement with clinical parameters and other molecular markers. For instance, combining DCPS expression analysis with indicators of glycemic control (e.g., glycated hemoglobin), inflammatory markers [e.g., C-reactive protein, interleukin-6 (IL-6)], and local wound microenvironment characteristics (e.g., angiogenic factors, cell proliferation-associated proteins) could allow differentiation between systemic influences and wound-specific regulatory effects on DCPS[37]. Such a multi-parameter approach not only improves the diagnostic precision of DCPS as a wound biomarker but also provides a more robust experimental basis for investigating its functional role in tissue repair.

Lack of standardized reference ranges: Currently, no standardized methods have been established for assessing DCPS expression in tissue or circulating samples, which substantially limits its feasibility for clinical application. Considerable variability exists among studies with respect to sample types—such as tissue sections, serum, or peripheral blood mononuclear cells—as well as analytical approaches, including immunohistochemistry, Western blot, quantitative PCR (qPCR), and enzyme-linked immunosorbent assay (ELISA), and the methods used for data normalization and standardization. These factors collectively contribute to low comparability and reproducibility across different studies[38]. For example, immunohistochemistry is highly sensitive to antibody specificity and staining conditions, whereas ELISA and qPCR results may be influenced by sample pre-processing, RNA quality, and the selection of internal controls[39]. The absence of unified experimental protocols and quantification standards makes it challenging for different laboratories to obtain consistent measurements of DCPS levels, thereby restricting its broader application in clinical diagnosis and prognostic evaluation. The study still lacks validation in a large, well-characterized, and demographically diverse patient cohort. Without clinical correlation across different stages of DFU, it remains uncertain whether DCPS expression reliably reflects disease severity, predicts healing trajectories, or identifies patients at high risk for ulcer recurrence in real-world settings.

To enable reliable clinical translation of DCPS, it is imperative to develop standardized detection protocols and reference ranges suitable for diverse patient populations. This entails not only optimizing and standardizing analytical techniques but also establishing appropriate reference intervals that account for patient-specific factors such as age, sex, comorbidities, and wound characteristics. Furthermore, multicenter validation using diverse sample sets and the implementation of rigorous quality control systems are critical to ensure inter-laboratory comparability and reproducibility. These measures would enhance the reliability of DCPS as a biomarker and lay a solid foundation for its clinical application in DFUs and other related disorders.

Unclear therapeutic potential: Despite in vitro evidence suggesting that DCPS promotes keratinocyte proliferation, migration, and survival, direct evidence demonstrating that targeted modulation of DCPS can accelerate wound healing in vivo remains lacking. In vitro experimental systems cannot fully recapitulate the complex tissue microenvironment, including blood supply, immune cell dynamics, inflammatory responses, and intercellular signaling, all of which critically influence wound repair[40,41]. Therefore, although DCPS exhibits potential to enhance keratinocyte function in vitro, its actual therapeutic efficacy in vivo requires careful evaluation.

Potential strategies for clinical translation include gene overexpression to enhance DCPS activity, the use of small-molecule activators, or epigenetic interventions targeting m7G-mediated RNA metabolism[42]. While theoretically capable of promoting wound repair, these approaches require rigorous preclinical validation to assess safety, effective dosing, tissue specificity, and potential off-target effects. Notably, the regulatory network linking m7G-mediated RNA metabolism and cell repair signaling remains incompletely understood, and indiscriminate modulation of DCPS may trigger unpredictable molecular or cellular consequences.

The need for multiple strategies

DFU is a highly complex, multifactorial condition, with its pathogenesis influenced by the interplay of chronic hyperglycemia, peripheral neuropathy, vascular dysfunction, local and systemic infections, persistent inflammation, and oxidative stress[43]. Given the multifaceted nature of DFU pathology, reliance on a single biomarker is insufficient for accurately assessing wound healing potential or guiding individualized therapeutic strategies. In this context, the diagnostic and therapeutic value of DCPS may be more pronounced when evaluated in conjunction with other biomarkers and clinical parameters. For instance, integrating DCPS expression with profiles of inflammatory cytokines (e.g., IL-6, TNF-α, interleukin-1β), angiogenic markers (e.g., vascular endothelial growth factor, CD31), and oxidative stress indicators (e.g., malondialdehyde, superoxide dismutase) could provide a more comprehensive assessment of wound healing capacity[30,33,44]. Such combined evaluation not only facilitates the elucidation of DCPS functional dynamics under varying inflammatory or metabolic states but also enhances disease specificity and mitigates inter-individual variability in predictive accuracy.

Therapeutically, combining DCPS-targeted interventions with established modalities—such as local growth factor administration, optimized glycemic control, stem cell therapy, or pro-angiogenic treatments—may exert synergistic effects by concurrently enhancing keratinocyte function, promoting neovascularization, and alleviating local inflammation, thereby accelerating wound closure and improving healing quality[43].

Moreover, a multifactorial combinatorial approach enables dynamic monitoring and adaptive adjustment of treatment regimens; by regularly assessing DCPS levels alongside relevant biomarkers, clinicians can tailor interventions according to the wound microenvironment, facilitating personalized and precision-guided therapy.

Future directions

Future research should systematically evaluate the reliability and clinical applicability of DCPS in the diagnosis and treatment of DFU, with particular emphasis on conducting prospective, multicenter, and large-scale clinical studies. Study designs should incorporate stratification based on ulcer severity, patient comorbidities (such as diabetic nephropathy, cardiovascular disease, or chronic inflammatory states), and prior treatment history (including local growth factor therapy, glycemic control levels, or previous surgical interventions) to enhance the generalizability and precision of findings[44]. Additionally, dynamic monitoring of DCPS expression throughout the wound healing process may reveal its temporal characteristics and predictive potential, clarifying its mechanistic role at different healing stages, including the inflammatory, proliferative, and remodeling phases, and providing valuable guidance for clinical intervention timing.

At the molecular level, future investigations should further elucidate how DCPS-mediated m7G modification regulates keratinocyte gene expression networks, including cell cycle regulators, migration-related proteins, and ECM remodeling factors, thereby influencing keratinocyte proliferation, migration, and differentiation. The role of DCPS in the wound microenvironment should also be explored, particularly its effects on immune cell recruitment, inflammation resolution, and angiogenic signaling, as well as its functional modulation under varying inflammatory or oxidative stress conditions[45]. These studies will provide a comprehensive understanding of DCPS-mediated molecular regulation in wound repair and offer mechanistic insights for precise therapeutic targeting.

Furthermore, targeted intervention strategies focusing on DCPS—such as gene overexpression, RNA modification modulation, or small-molecule activators—should be systematically assessed in vivo in DFU models to evaluate their efficacy and safety. Integrating mechanistic research with functional intervention studies will facilitate optimization of therapeutic approaches, enabling personalized treatment strategies and providing prospective evidence for future clinical trials. Such research not only clarifies the critical role of DCPS in DFU healing but also lays a scientific foundation for developing novel RNA metabolism-based therapeutic strategies, ultimately contributing to more effective, individualized wound management and improved healing outcomes in clinical practice.

Conclusion

DCPS establishes a crucial molecular link between RNA methylation and the pathophysiology of chronic wounds, highlighting its potential utility in the early diagnosis, disease assessment, and therapeutic intervention of DFUs. However, the clinical translation of DCPS remains challenging. Its disease specificity is limited, as DCPS expression can be influenced by systemic factors commonly observed in diabetic patients, including glycemic status, chronic inflammation, metabolic syndrome, and comorbidities, thereby potentially compromising its accuracy as a standalone biomarker for DFU. Moreover, the absence of standardized detection methods and reference ranges restricts the comparability and reproducibility of data across different laboratories or clinical centers. To address these limitations, integrating DCPS assessment with other molecular biomarkers and clinical parameters may provide a more comprehensive, multidimensional evaluation, enabling personalized disease management. Future studies should focus on prospective, multicenter, and stratified clinical investigations, combined with dynamic monitoring and targeted intervention strategies, to systematically evaluate the functional role and therapeutic potential of DCPS across diverse pathological conditions and treatment modalities. Such efforts will not only offer novel insights into DFU management but also lay a theoretical foundation for RNA metabolism-based innovative therapeutic approaches, ultimately advancing the field of chronic wound care toward precision medicine and individualized treatment.