Diabetic foot ulcers (DFU) are one of the most serious complications of diabetes and a leading cause of lower extremity amputations. Successful wound healing relies on tightly coordinated inflammation, fibroblast proliferation, extracellular matrix remodeling, and tissue remodeling. However, in diabetes, hyperglycemia and metabolic stress can lead fibroblasts to undergo cellular senescence and release persistent senescence-associated secretory phenotype (SASP) factors that damage the wound environment. RNA-binding proteins (RBPs), which control RNA stability and gene expression, are novel regulators of tissue repair, but their role in DFU remains unclear. Based on these questions, detailed studies are needed to elucidate how RNA-binding proteins regulate fibroblast senescence and impaired wound healing in diabetic foot ulcers.
Researchers from the Department of Endocrinology, First Affiliated Hospital of Anhui Medical University and the Institute of Endocrinology and Metabolism of Anhui Medical University reported the study (DOI: 10.1093/burnst/tkag021). burns and trauma This article reveals how. interleukin enhancer binding factor 2 (ILF2) proteins regulate nucleophosmin 1 (NPM1) and nuclear factor kappa-B (NF-κB) signaling to control inflammatory aging in diabetic wound repair.
The research team first identified RBPs that were altered in DFU fibroblasts by analyzing publicly available single-cell RNA-seq and bulk transcriptome datasets. ILF2 emerged as an important downregulated candidate and was validated in clinical DFU tissues, diabetic mouse wounds, and high glucose-treated fibroblasts. Functional experiments showed that overexpression of ILF2 promoted fibroblast proliferation and migration, while suppressing SASP factors such as interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinase-1 (MMP1), and matrix metalloproteinase-3 (MMP3). In contrast, ILF2 knockdown exacerbated inflammatory aging and weakened fibroblast repair function. Mechanical assays such as RNA-seq, RNA immunoprecipitation (RIP), RNA pull-down, and RNA stability testing NPM1 Messenger RNA (mRNA) as a direct target of ILF2. ILF2 protein is bound NPM1 By degrading mRNA and promoting its degradation, it prevents excessive accumulation of NPM1 protein. Deficiency of ILF2 resulted in accumulation of NPM1 protein, enhanced interaction with p65, activation of NF-κB signaling, and increased SASP expression. Rescue experiments showed that knockdown of NPM1 rescued the fibroblast dysfunction caused by loss of ILF2. In diabetic mice, overexpression of ILF2 promoted wound closure, whereas knockdown of ILF2 delayed healing. Knockdown of NPM1 also improved repair and attenuated inflammatory aging.
The authors said this study reframes diabetic wound repair not only as a problem of blood supply, infection, and surface tissue damage, but also as a failure to control RNA levels within fibroblasts. They said ILF2 appears to act as a molecular brake that prevents inflammatory aging from becoming excessive. When this brake is lost, NPM1 accumulates, NF-κB signaling becomes excessive, and fibroblasts are unable to support wound repair. Restoring this balance may provide a more precise route to restarting healing in chronic diabetic wounds, the researchers said.
This finding identifies the ILF2-NPM1-NF-κB regulatory axis as a promising target for future DFU therapy. Rather than broadly suppressing inflammation, treatments designed to restore ILF2 activity or limit NF-κB activation by NPM1 may help reduce deleterious fibroblast senescence while preserving cellular functions necessary for repair. This study also expands our understanding of RBPs in chronic wound biology and suggests that post-transcriptional regulation is an important layer of diabetic tissue repair. Further studies will be required to elucidate why ILF2 is downregulated in diabetic wounds and whether approaches targeting ILF2 or NPM1 can be safely developed for clinical wound treatment.
sauce:
Chinese Academy of Sciences
Reference magazines:
Ji, H, others. (2026) Mechanism of RNA-binding protein ILF2 in promoting diabetic foot ulcer wound healing through regulation of the NPM1/NF-κB axis. burns and trauma. DOI: 10.1093/burnst/tkag021. https://academic.oup.com/burnstrauma/advance-article/doi/10.1093/burnst/tkag021/8526249
