Circular RNAs in Diabetic Foot Ulcers: A Scoping Review of Clinical, Preclinical, and In Silico Evidence on Diagnostic and Therapeutic Potentials

Abstract

Background and objective: Diabetic foot ulcers (DFUs) involve chronic inflammation, impaired angiogenesis, oxidative stress, and disrupted fibroblast-keratinocyte interactions. Circular RNAs (circRNAs), a category of stable non-coding RNAs, have become essential regulators of these processes; nevertheless, their comprehensive functions in DFUs are still inadequately characterised. This scoping review integrated clinical, preclinical, and in silico evidence on circRNAs in DFUs to assess their diagnostic, mechanistic, and therapeutic potential.

Methods: Systematic searches of MEDLINE, EMBASE, Web of Science, and Google Scholar were conducted on July 16, 2025, according to the PRISMA-ScR guidelines. Eligible papers included clinical investigations of circRNAs in the tissues of patients with DFUs, preclinical animal models assessing circRNA-based therapies, and computational predictions of circRNA-miRNA-mRNA networks. Information was collected on circRNA expression, molecular targets, clinical associations, and therapeutic effects.

Results: Twenty-two studies (7 clinical, 13 preclinical, 2 in silico) were selected. Clinical studies found hsa_circ_PRKDC, hsa_circ_072697, hsa_circ_080968, and hsa_circ_0000907 to be associated with wound severity, tissue perfusion, and keratinocyte proliferation in patients with diabetic foot ulcers. Preclinical studies showed that delivery of mmu_circHIPK3, mmu_circMYO9B, and mmu_circ_Astn1 via exosomes or nanoparticles improved angiogenesis, epithelial regeneration, and wound closure. However, the silence of mmu_circ_0005654 reduced ferroptosis and inflammation. In silico analyses identified potential regulatory axes, such as hsa_circ_0089761/miR-146a-5p/SMAD4 (Mothers against decapentaplegic homologue 4) and hsa_circ_0049271/miR-24-3p/JUNB, that were associated with inflammatory-angiogenic pathways in this disease.

Conclusions: CircRNAs hold promise for the diagnosis and treatment of DFUs by modulating angiogenesis, inflammation, oxidative stress, and epithelial repair. Standard network-guided therapies are essential to translate circRNA-based strategies into clinical practice.

Keywords: angiogenesis; biomarker; circular RNA; diabetic foot ulcer; exosomal therapy; in silico network; non‐coding RNA; wound healing.