ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Molecular and Cellular Pathology
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1606716
This article is part of the Research TopicAdvances in Skin Barrier Dysfunction and Disease PathogenesisView all 3 articles
Saliva-Derived Exosomes Regulate Fibroblast Metabolic Reprogramming in Skin Wound Healing
Provisionally accepted
- Department of Operative Dentistry and Endodontology, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China
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Background: Effective skin repair requires rapid wound closure accompanied by precise extracellular matrix (ECM) remodeling and balanced cellular metabolism. Saliva-derived exosomes (S-Exo) have emerged as promising therapeutic agents due to their rich bioactive components; however, their mechanisms in ECM remodeling and metabolic regulation remain unclear. This study aimed to elucidate how S-Exo modulate ECM turnover through metabolic reprogramming, particularly glycolysis, in human skin fibroblasts (HSFs), and identify critical exosomal molecules mediating these effects.Methods: S-Exo were isolated and characterized. A rat full-thickness skin defect model and in vitro assays with human skin fibroblasts and HaCaT keratinocytes were employed to evaluate S-Exo effects on wound closure, ECM remodeling, and cellular metabolism. Transcriptomic profiling of wound tissues, targeted metabolomic analysis of fibroblasts, and proteomic evaluation of S-Exo cargo were performed to explore underlying mechanisms. Metabolic interventions further confirmed the contribution of metabolic modulation to S-Exo-mediated wound healing.Results: S-Exo significantly accelerated wound healing by enhancing fibroblast viability, migration, and ECM remodeling, characterized by elevated secretion of matrix metalloproteinases (MMP1 and MMP3). Transcriptomic, metabolomic, and proteomic analyses revealed that S-Exo robustly activated key metabolic pathways, particularly glycolysis, reflected by increased expression of glycolytic genes (e.g., GLUT1, HK2, PFKM) and enhanced glycolytic flux in fibroblasts.Remarkably, S-Exo were found to carry nearly all enzymes involved in glycolysis, indicating an underlying enzyme-transfer mechanism for sustained metabolic modulation. Importantly, glycolytic activity positively correlated with MMP secretion, and inhibition of glycolysis significantly reduced MMP production, highlighting glycolysis as a crucial regulator of ECM remodeling.Conclusions: Saliva-derived exosomes promote wound healing by potentially modulating fibroblast metabolism via exosome-associated glycolytic enzymes, enhancing glycolytic flux, and thereby regulating ECM remodeling via increased MMP secretion. These findings provide novel insights into metabolism-targeted exosome therapies for wound healing.
Keywords: Saliva-derived exosomes, Glycolysis, metabolic reprogramming, Wound Healing, extracellular matrix remodeling, Fibroblasts
Received: 06 Apr 2025; Accepted: 14 Jul 2025.
Copyright: © 2025 SONG, Xiang, Chen, Wu, Chen and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wenxia Chen, Department of Operative Dentistry and Endodontology, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China
Xianyu Li, Department of Operative Dentistry and Endodontology, College of Stomatology, Hospital of Stomatology, Guangxi Medical University, Nanning, China
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