Abstract

BackgroundDiabetic foot ulcer (DFU) is a severe diabetic complication characterized by impaired healing, often involving fibroblast senescence and the senescence-associated secretory phenotype (SASP). The role of RNA-binding proteins (RBPs) in this process remains undefined. This study investigates the function and mechanism of the RBP Interleukin enhancer-binding factor 2 (ILF2) in DFU pathogenesis.MethodsDifferentially expressed RBPs were identified via bioinformatics analysis of public single-cell and bulk transcriptomic datasets. ILF2 downregulation was subsequently validated in clinical DFU samples and diabetic mouse models. Functional assays in high-glucose-treated fibroblasts evaluated proliferation, migration, and SASP. Mechanistically, RNA sequencing, RIP, and RNA pull-down assays identified downstream targets, while co-IP and rescue experiments verified the NPM1/NF-κB axis. Finally, a diabetic mouse model was used to study the effects of ILF2 overexpression/knockdown and NPM1 knockdown on wound healing.ResultsBioinformatics analysis identified ILF2 as significantly downregulated in DFU. This reduction was consistently validated in DFU patient tissues, diabetic mouse wounds, and high-glucose-treated fibroblasts. Functionally, ILF2 overexpression promoted fibroblast proliferation and migration while suppressing SASP, whereas knockdown exacerbated senescence. Mechanistically, ILF2 directly bound to Nucleophosmin (NPM1) mRNA to promote its degradation. ILF2 deficiency led to aberrant NPM1 accumulation, enhancing the NPM1-p65 interaction and NF-κB pathway activation. Rescue experiments confirmed that NPM1 knockdown reversed ILF2 deficiency-induced cellular dysfunction. Crucially, these findings were validated in primary fibroblasts isolated from DFU patients. In vivo, ILF2 overexpression accelerated wound healing, while knockdown delayed the process. Furthermore, NPM1 knockdown effectively ameliorated the impaired healing phenotype and reduced SASP levels.Conc