Analyzing Immune Cell Infiltration and Copper Metabolism in Diabetic Foot Ulcers

Abstract

Background Diabetes impairs wound healing, notably in diabetic foot ulcers (DFU). Stress, marked by the accumulation of lipoylated mitochondrial enzymes and the depletion of Fe–S cluster proteins, triggers cuproptosis—a distinct form of cell death. The involvement of copper in the pathophysiology of DFU has been recognized, and currently, a copper-based therapeutic strategy is emerging as a viable option for enhancing ulcer healing. This study investigates genes linked to copper metabolism in DFU, aiming to uncover potential targets for therapeutic intervention. Methods Two diabetic wound Gene Expression Omnibus (GEO) datasets were analyzed to study immune cell dysregulation in diabetic wounds. Differentially expressed genes related to copper metabolism were identified and analyzed using machine learning methods. Gene ontology, pathway enrichment, and immune infiltration analyses were performed using DFU samples. The expression of identified genes was validated using qRT-PCR and single-cell RNA sequencing. Results Ten genes associated with copper metabolism were identified. Among these, SLC31A1 and ADNP were found to be significantly differentially expressed in DFU. Notably, SLC31A1 exhibited higher expression in macrophages, whereas ADNP was found to be highly expressed in fibroblasts and chondrocytes. Conclusion The study indicates a close link between copper metabolism, the infiltration of immune cells, and DFU. It proposes that copper metabolism could influence the progression of DFU through the activation of immune responses. These observations offer fresh perspectives on the underlying mechanisms of DFU and identify potential targets for therapeutic intervention.

Multi-omic validation of the cuproptosis-sphingolipid metabolism network: modulating the immune landscape in osteosarcoma

“…Copper is an essential trace element involved in the activity and function of multiple enzymes, significantly impacting cellular energy production, neural conduction, antioxidative defense, and the absorption and metabolism of iron (18)(19)(20)(21). The relationship between copper ion metabolism and tumor development has become increasingly clear, particularly with the discovery of a new mode of cell death induced by copper-cuproptosis (22,23).…”

Integrating bioinformatics and multiple machine learning to identify mitophagy-related targets for the diagnosis and treatment of diabetic foot ulcers: evidence from transcriptome analysis and drug docking

“…However, the current clinical diagnosis and treatment of DFU also face challenges, with the clinical diagnosis of DFU being overly dependent on the clinical experience of clinicians and lacking effective treatments ( Armstrong et al, 2017 ; Matos et al, 2018 ; Purwanti et al, 2024 ; Wang F. et al, 2024 ; Wang K. et al, 2024 ). At the present stage, the treatment of DFU patients mainly includes debridement, wound dressing, anti-infection treatment, peripheral vasculopathy treatment, strict glycemic control, and amputation ( McIllhatton et al, 2021 ; Orlando et al, 2021 ; Ahmed et al, 2022 ; Slomski, 2022 ; Jeffcoate et al, 2024 ), but the therapeutic efficacy of these methods is still unsatisfactory and has not yet achieved a satisfactory clinical results, that is, they do not fully control the underlying metabolic lesions ( Bardill et al, 2022 ; Chen et al, 2024 ; Yi et al, 2024 ; Zhang G. et al, 2024 ; Zhang N. et al, 2024 ). Thus, it is urgent to further identify novel biomarkers of DFU to improve the current dilemma of clinical diagnosis and treatment of DFU.…”