Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing

Diabetic foot ulcers (DFUs) are a severe, life-threatening condition that often lead to lower limb amputations and reduced life expectancy. Despite their clinical significance, the molecular mechanisms driving DFU pathogenesis remain poorly understood. Using next-generation sequencing, we generated a human dataset of pathogenic DFUs and compared it to transcriptional profiles from human skin and oral acute wounds. The oral model was chosen as an example of “ideal” adult tissue repair, characterized by rapid closure without scarring. Our analysis revealed key transcriptional networks disrupted in DFUs, leading to impaired recruitment of neutrophils and macrophages and an overall dysregulated inflammatory response. Notably, the transcription factors FOXM1 and STAT3, which are crucial for activating and promoting immune cell survival, were found to be inhibited in DFUs. Further, inhibition of FOXM1 in diabetic mouse models (both STZ-induced and db/db) resulted in delayed wound healing and reduced neutrophil and macrophage recruitment in diabetic wounds. These findings highlight the role of a defective, ineffective inflammatory response as a major contributor to DFU pathogenesis, driven by FOXM1-mediated disruption of immune cell recruitment.FDI-6 This suggests that targeting FOXM1 could offer a potential therapeutic strategy for improving DFU healing.