Letter to the Editor: Unveiling the role of decapping scavenger enzyme in diabetic foot ulcers: Linking N7-methylguanosine RNA modification to impaired wound healing

Abstract

Diabetic foot ulcer (DFU), a common complication of diabetes, is often associated with non-healing wounds that can eventually lead to infection and amputation. Epitranscriptomic modifications have been shown to have an important impact on metabolic diseases. Recently, a study by Xiao et al published in World Journal of Diabetes focused on the role of the N7-methylguanosine-related decapping scavenger enzyme (DCPS) in DFU. They found that DCPS is linked to keratinocyte dysfunction in DFU and that in DFU tissue and diabetic mouse skin, DCPS is significantly down-regulated. Silencing DCPS induces cell cycle arrest and apoptosis, thereby inhibiting keratinocyte proliferation and migration. These findings suggest that impaired RNA cap turnover and mRNA decay may lead to defective wound healing in diabetes-a mechanism that is different from changes in RNA methylation alone. This study highlights DCPS as a potential biomarker and therapeutic target for treatment of diabetic wounds.

Key Words: Diabetic foot ulcer; N7-methylguanosine modification; Decapping scavenger enzyme; Keratinocyte; RNA metabolism; Wound healing

Core Tip: Reduced expression of the N7-methylguanosine decapping scavenger enzyme (DCPS) has been observed in diabetes and associated with impaired keratinocyte regeneration. DCPS may work as a useful biomarker and therapeutic target for improving wound healing in diabetes.

TO THE EDITOR

Chronic/non-healing wounds, especially diabetic foot ulcer (DFU), have posed a major challenge to diabetes care, as it may lead to significant morbidity, disability, and huge healthcare costs worldwide[1,2]. Although wound management has achieved great improvements, the pathogenesis of DFU is still not fully understood due to its multifactorial nature, involving ischemia, neuropathy, infection, oxidative stress, and impaired cellular regeneration[3-5].

Recently, epitranscriptomics-the study of RNA modifications-has emerged as a key aspect of metabolic disease research. Some studies showed N7-methylguanosine (m⁷G), a central epitranscriptomic mark, could regulate RNA stability, splicing, translation, and decay[6,7]. Dysregulated RNA methylation has proved to be related with cancer, neurodegeneration, and diabetic complications[8,9]. However, the role of m⁷G in diabetic wound healing remains not clear enough.

Decapping scavenger enzyme and m⁷G modification: An unexpected connection

The decapping scavenger enzyme (DCPS) acts in the final step of mRNA decay—hydrolyzing, where the residual m⁷GpppN cap is hydrolyzed after 3′- 5′ exonucleolytic degradation[10,11]. Through this process, DCPS helps recycle m⁷G caps and maintain mRNA turnover, thus supporting transcriptome homeostasis[12]. Previous studies have linked DCPS dysfunction to neurodevelopmental disorders and cellular stress responses. However, its role in tissue repair has not been well studied[13].

In the study by Xiao et al[14] published in the recent issue of the World Journal of Diabetes, DCPS expression was lower in DFU tissues than in normal skin and diabetic non-ulcerated skin. When DCPS was knocked down in human keratinocytes, the cells showed G₂-phase arrest, increased apoptosis, and reduced migration. These changes were associated with impaired epidermal regeneration and wound healing. Together, these observations suggest that altered RNA cap turnover and mRNA decay may be involved in keratinocyte dysfunction in diabetic wounds, beyond changes in RNA methylation alone.

RNA modification and wound healing: Beyond translational control

Wound healing is a dynamic and highly programmed process that requires coordinated cell proliferation, migration, angiogenesis, and matrix remodeling[15]. Emerging evidence has showed that under metabolic stress, RNA modifications could help fine-tune the translation of wound-healing-associated key genes[16]. Among these modifications, m⁷G, m⁶A, and pseudouridine play an important role in regulating RNA stability and ribosome recruitment in oxidative environments[17].

In diabetic wounds, sustained hyperglycemia and inflammation are regarded as the main disruptors of these epitranscriptomic networks[18]. The current findings on DCPS revealed a novel mechanism: The impaired m⁷G cap turnover may cause abnormal mRNA accumulation, and disrupt the synthesis of the key proteins for keratinocyte migration. This mechanism provides a potential explanation for the chronic, hard-to-heal characteristic of DFU and aligns with the broader view that the disorder of RNA metabolism may contribute to metabolic tissue degeneration.

Translational implications: DCPS as a biomarker and therapeutic target

In practical terms, DCPS could be consider as both a diagnostic biomarker and a therapeutic target. Reduced expression in DFU tissue may reflect impaired regenerative capacity and poor healing potential. Furthermore, restoring DCPS function by pharmacological or genetic strategies may help re-establish RNA homeostasis and promote epidermal cell-cycle progression.

Notably, even though RNA methylation modulation has been wildly explored in oncology and neurodegeneration[19,20], its application in diabetic wound therapy remains poorly explored. Local or topical approaches could be used to modulate DCPS activity directly in the wound area, which may help limit systemic effects. More work is still needed to assess the safety of targeting RNA cap metabolism.

Limitations and future directions

Even though this study[14] brought some new perspectives, some key questions remain to be answered. First, it is unclear whether the DCPS downregulation is a cause or a consequence of chronic inflammation in diabetic wounds, and longitudinal in vivo studies are warranted to address this issue. Second, the upstream regulatory mechanisms controlling DCPS expression under hyperglycemic and oxidative stress is still unknown so far, and the potential mediators could be transcription factors or metabolic sensors. Third, potential interactions between DCPS and other epitranscriptomic pathways (e.g., m⁶A and m⁵C) need further investigation. Finally, validation in larger patient cohorts and the development of agents that can selectively target DCPS activity will be essential for future clinical translation.

Conclusion

In their study, Xiao et al[14] showed that DCPS is involved in keratinocyte function in DFU. Their findings also suggest a role for impaired RNA cap turnover in chronic wound healing and helps improve our understanding the mechanisms of chronic wound healing. By linking impaired epithelial repair with m⁷G RNA cap metabolism defects, this work reveals a novel mechanism that integrates RNA dynamics with metabolic tissue dysfunction. Future work should focus on the mechanism of how DCPS is regulated and evaluate the therapeutic potential of restoring its function. Integrating epitranscriptomic regulation into wound treatments may provide new insights for improving clinical outcomes in DFU.