Targeting Signalling Pathways in Chronic Wound Healing

Abstract

Chronic wounds fail to achieve complete closure and are an economic burden to healthcare systems due to the limited treatment options and constant medical attention. Chronic wounds are characterised by dysregulated signalling pathways. Research has focused on naturally derived compounds, stem-cell-based therapy, small molecule drugs, oligonucleotide delivery nanoparticles, exosomes and peptide-based platforms. The phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT), Wingless-related integration (Wnt)/β-catenin, transforming growth factor-β (TGF-β), nuclear factor erythroid 2-related factor 2 (Nrf2), Notch and hypoxia-inducible factor 1 (HIF-1) signalling pathways have critical roles in wound healing by modulating the inflammatory, proliferative and remodelling phases. Moreover, several regulators of the signalling pathways were demonstrated to be potential treatment targets. In this review, the current research on targeting signalling pathways under chronic wound conditions will be discussed together with implications for future studies.

Keywords: HIF-1; Notch; Nrf2; PI3K/AKT; TGF-β; Wnt/β-catenin; chronic wound healing; exosomes; naturally derived compounds; oligonucleotide delivery nanoparticles; peptide-based platforms; signalling pathways; small molecules drugs; stem-cell-based therapy.

Figure 1

An overview of the wound healing process and the signalling processes involved in the inflammatory, proliferative, and remodelling phases. Abbreviations: PI3K: phosphoinostide-3-kinase; AKT: protein kinase B; Nrf2: nuclear factor erythroid 2-related factor 2; TGF-β: transforming growth factor-β; HIF-1: hypoxia inducible factor-1; Wnt: Wingless/integrated. Created with Biorender.com. Accessed on 5 December 2023.

Figure 2

A comparison of acute inflammation in normal wound healing versus chronic inflammation exhibited by a chronic wound. Created with Biorender.com.

Figure 3

An overview of the effect of currently investigated treatment strategies in targeting PI3K/AKT, Nrf2, TGF-β, Notch and HIF-1 signalling pathways to promote chronic wound healing. Abbreviations: PI3K: phosphoinostide-3-kinase; AKT: protein kinase B; Nrf2: nuclear factor erythroid 2-related factor 2; TGF-β: transforming growth factor-β; HIF-1: hypoxia inducible factor-1; PHD2: prolyl hydroxylase domain protein 2; VHL: von Hippel–Lindau. Created with BioRender.com. Accessed on 5 December 2023.