Table 3.

Mechanisms of action (MOA) of honey contributing to wound healing and the related studies.

MOA	Descriptions of honey MOA	Related studies
Antimicrobial	QS and microbial biofilm disruption, leading to the loss of microbial coordinated responses, fail to secrete virulence factors and eventually become harmless and defenseless. 33 Honey inhibits bacterial cell adhesion to surfaces, suppressing their metabolic activities, and downregulating the global QS regulator genes, eventually preventing biofilm development. 34	A 2011 study by Lee et al. demonstrated that honey concentration at as low as 0.5% (v/v) could reduce the biofilm formation of Escherichia coli. 35 Their transcriptomic study also revealed that honey can inhibit biofilm‐related curli genes, QS genes, and virulence genes in E. coli, mainly attributed to the glucose and fructose in the honey. 35 A 2014 study by Lu et al. showed that Manuka honey can inhibit biofilm formation due to the diffusion of MGO compound into the biofilm matrix and acts by killing the bacteria. 36 A 2021 study by Proaño et al. showed that the synergistic effects of the high sugar concentration, the presence of hydrogen peroxide, and bee defensin‐1 peptide in honey suppress the biofilm formation. 37
Anti‐inflammatory	Honey reduces prostaglandin levels in the plasma by impeding the activity of COX1 and COX2; attenuating the NF‐κB, inhibiting the expression of TNF‐α and NO, eventually reducing inflammation. 38	N/A
Antioxidant	The flavonoids and phenolics of the honey inhibit the superoxide anions‐producing enzymes and thus reduce the production of ROS and RNS. 38	N/A
Proangiogenic	Honey stimulates angiogenesis, an essential part of the proliferative phase of wound healing.	A 2010 in vitro angiogenesis analogues study by Rossiter et al. showed that honey exerted its proangiogenic effects at as low as 0.1%−1.0% (v/v). 39 They showed that honey was as strong a stimulator of pseudotubule formation as VEGF in the rat aortic ring assay, indicating the potency of honey to stimulate blood vessel formation. 39 A 2020 in vivo study by Chaudhary et al. demonstrated significant wound closure, reepithelialization, and collagen deposition in the diabetic mice model upon application of 0.1% (v/v) Jamun honey. 40
Immunomodulation	Honey promotes the release or activation of immune system mediators, stimulates the mitogenesis of B and T lymphocytes, and activates neutrophils and macrophages to remove potential infection‐causing pathogens. 38 The level of serum antibodies (IgM, IgG, and IgA) are augmented by honey to eliminate the infection‐causing organisms. 41	A 2007 study by Tonks et al. showed that honey can modulate the TLR4 pathway by inducing the production of TNF‐α and IL‐1β, which in turn stimulates the release of PDGF, which is crucial in fibroblast development for tissue repair. 42

Abbreviations: COX1 and 2, cyclooxygenases 1 and 2; IL‐1β, interleukin‐1β; MGO, methylglyoxal; N/A, non‐applicable; NF‐κB, nuclear factor kappa B; NO, nitric oxide; PDGF, platelet‐derived growth factor; QS, quorum sensing; RNS, reactive nitrogen species; ROS, reactive oxygen species; TLR4, toll‐like receptors 4; TNF‐α, tumor necrosis factor‐alpha; VEGF, vascular endothelial growth factor.