Diabetic foot ulcer (DFU) is one of the most serious complications of diabetes and a major cause of lower-limb amputation. Successful wound healing depends on tightly coordinated inflammation, fibroblast proliferation, extracellular matrix remodeling, and tissue reconstruction. In diabetes, however, high glucose and metabolic stress can push fibroblasts into cellular senescence, causing them to 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 emerging regulators of tissue repair, but their role in DFU remains unclear. Based on these challenges, in-depth research is needed to clarify how RNA-binding proteins regulate fibroblast senescence and impaired wound healing in diabetic foot ulcers.
Researchers from the Department of Endocrinology, The First Affiliated Hospital of Anhui Medical University, and the Institute of Endocrinology and Metabolism, Anhui Medical University, reported (DOI: 10.1093/burnst/tkag021) the study in Burns & Trauma on 17 March 2026. The article reveals how interleukin enhancer-binding factor 2 (ILF2) protein regulates nucleophosmin 1 (NPM1) and nuclear factor kappa-B (NF-κB) signaling to control inflammatory senescence in diabetic wound repair.
The team first analyzed public single-cell RNA sequencing and bulk transcriptomic datasets to identify RBPs that were altered in DFU fibroblasts. ILF2 emerged as a key downregulated candidate and was then validated in clinical DFU tissues, diabetic mouse wounds, and high-glucose-treated fibroblasts. Functional experiments showed that ILF2 overexpression promoted fibroblast proliferation and migration, while suppressing SASP factors, including interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinase-1 (MMP1), and matrix metalloproteinase-3 (MMP3). By contrast, ILF2 knockdown worsened inflammatory senescence and weakened fibroblast repair functions. Mechanistic assays, including RNA sequencing, RNA immunoprecipitation (RIP), RNA pull-down, and RNA stability tests, identified the NPM1 messenger RNA (mRNA) as a direct ILF2 target. ILF2 protein bound to NPM1 mRNA and promoted its degradation, thereby preventing excessive NPM1 protein accumulation. When ILF2 was deficient, NPM1 protein accumulated, strengthened its interaction with p65, activated NF-κB signaling, and increased SASP expression. Rescue experiments showed that NPM1 knockdown reversed the fibroblast dysfunction caused by ILF2 loss. In diabetic mice, ILF2 overexpression accelerated wound closure, whereas ILF2 knockdown delayed healing; NPM1 knockdown also improved repair and reduced inflammatory senescence.
The authors said the study reframes diabetic wound repair as not only a problem of blood supply, infection, or surface tissue damage, but also a failure of RNA-level control inside fibroblasts. They said ILF2 appears to act as a molecular brake that keeps inflammatory senescence from becoming excessive. When this brake is lost, NPM1 builds up, NF-κB signaling becomes overactive, and fibroblasts become less able to support wound repair. Restoring this balance, they said, may offer a more precise route to help chronic diabetic wounds restart healing.
The findings identify the ILF2–NPM1–NF-κB regulatory axis as a promising target for future DFU treatment. Instead of broadly suppressing inflammation, therapies designed to restore ILF2 activity or limit NPM1-driven NF-κB activation may help reduce harmful fibroblast senescence while preserving the cellular functions needed for repair. The study also expands understanding of RBPs in chronic wound biology, suggesting that post-transcriptional regulation is an important layer in diabetic tissue repair. Further work will be needed to determine why ILF2 becomes downregulated in diabetic wounds and whether ILF2- or NPM1-targeted approaches can be safely developed for clinical wound care.
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DOI
10.1093/burnst/tkag021
Original Source URL
https://doi.org/10.1093/burnst/tkag021
Funding information
Natural Science Foundation of Anhui Province in China, grant no. 2108085MH269; Anhui Provincial Health Research Project, grant no. AHWJ2023BAc10012.
About Burns & Trauma
Burns & Trauma is an open access, peer-reviewed journal publishing the latest developments in basic, clinical, and translational research related to burns and traumatic injuries, with a special focus on various aspects of biomaterials, tissue engineering, stem cells, critical care, immunobiology, skin transplantation, prevention, and regeneration of burns and trauma injury.