Diabetic foot ulcer (DFU) is one of the most serious complications of diabetes and a leading cause of lower limb amputation. Successful wound healing depends on tightly coordinated inflammation, fibroblast proliferation, extracellular matrix remodeling, and tissue remodeling. In diabetes, however, high glucose and metabolic stress can drive 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 elucidate 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 March 17, 2026. The article reveals how interleukin 2 enhancer binding factor (ILF2) Protein modulates 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 massive transcriptome datasets to identify RBPs that were altered in DFU fibroblasts. ILF2 emerged as a key down-regulated candidate and was subsequently validated in clinical DFU tissues, diabetic mouse wounds, and fibroblasts treated with high glucose. 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), metalloproteinase-1 (MMPloproteinx), and matrix matrix. In contrast, knockdown of ILF2 exacerbated inflammatory senescence and impaired repair functions of fibroblasts. Mechanistic assays, including RNA sequencing, RNA immunoprecipitation (RIP), RNA pull-down, and RNA stability assays, identified NPM1 messenger RNA (mRNA) as a direct target of ILF2. The ILF2 protein binds to NPM1 mRNA and promoted its degradation, thereby preventing excessive accumulation of NPM1 protein. When ILF2 was deficient, NPM1 protein accumulated, enhanced its interaction with p65, activated NF-κB signaling, and increased SASP expression. Rescue experiments showed that knockdown of NPM1 reversed the fibroblast dysfunction caused by the loss of ILF2. In diabetic mice, ILF2 overexpression accelerated wound closure, while ILF2 depletion delayed healing. NPM1 knockdown also improved repair and reduced inflammatory senescence.
The authors said the study redefines diabetic wound repair not only as a problem of blood supply, infection or surface tissue damage, but also as a failure to control the level of RNA 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 hyperactive, and fibroblasts become less able to support wound repair. Restoring that balance, they said, may provide a more precise route to help chronic diabetic wounds start healing again.
The findings identify the ILF2-NPM1-NF-κB regulatory axis as a promising target for future DFU therapy. Instead of broadly suppressing inflammation, therapies designed to restore ILF2 activity or limit NPM1-driven NF-κB activation may help reduce deleterious fibroblast senescence while preserving cellular functions required for repair. The study also extends the 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 is downregulated in diabetic wounds and whether approaches targeting ILF2 or NPM1 can be safely developed for clinical wound care.
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