Chengcheng Liu,1, Xueli Niu,2,3, Yunfa Xu,4 Wei Liu5 1Department of Rehabilitation, Shengjing Hospital of China Medical University, Shenyang, Liaoning, Peopleâs Republic of China; 2Department of Dermatology, The First Hospital of China Medical University, Shenyang, Liaoning, Peopleâs Republic of China; 3Key Laboratory of Immunodermatology, Ministry of Education and NHC; National Joint Engineering Research Center for Theranostics of Immunological Skin Diseases, Shenyang, Liaoning, Peopleâs Republic of China; 4Department of Radiology, Shenyang Second Hospital of Traditional Chinese Medicine, Shenyang, Liaoning, Peopleâs Republic of China; 5Department of Neurology, Shenyang Second Hospital of Traditional Chinese Medicine, Shenyang, Liaoning, Peopleâs Republic of ChinaThese authors contributed equally to this workCorrespondence: Wei Liu; Yunfa Xu, Email 18940159345@163.com; 1976443579@qq.comAbstract: Diabetic wound healing impairment represents a pressing clinical challenge worldwide, with its high disability rate and recurrence rate imposing a heavy burden on patients and healthcare systems. Keratinocytes are the core effector cells that drive re-epithelialization during wound healing, and their impaired proliferative capacity is a core pathological mechanism underlying healing arrest and chronic wound development. The functional status of other repair cell populations, including fibroblasts, endothelial cells and immune cells, also exerts direct or indirect regulatory effects on the entire wound healing process. Under diabetic conditions, multifaceted pathological changes triggered by hyperglycemia not only induce comprehensive functional impairment of keratinocytes, but also disrupt the synergistic interaction between various repair cells. This ultimately stalls the physiological wound healing cascade, leading to the development of chronic, non-healing wounds. Building upon this, this review further summarizes novel targeted therapeutic strategies addressing these mechanisms, encompassing cutting-edge approaches such as engineered exosome delivery systems, photobiomodulation therapy, metabolic enzyme small-molecule inhibitors, peptide agonists, and plant-derived nanovesicles. This review aims to delineate the crosstalk between core regulatory modules and identify key druggable targets, a theoretical framework for the development of precision combination therapies with multi-target synergistic effects. Existing evidence demonstrates that the synergistic dysfunction of multiple core molecular hubs represents the core pathological basis underlying suppression in diabetic wounds. Future therapeutic strategies should focus on the synergistic benefits of spatiotemporally controlled dynamic intervention and wound microenvironment reprogramming. Keywords: diabetic wounds, keratinocytes, proliferation inhibition, targeted therapy, metabolic reprogramming, epigenetic regulation, extracellular matrix, exosomes
Liu et al. (Wed,) studied this question.