2. Academic Validation
  3. Artesunate attenuates skin hypertrophic scar formation by inhibiting fibroblast activation and EndMT of vascular endothelial cells

Artesunate attenuates skin hypertrophic scar formation by inhibiting fibroblast activation and EndMT of vascular endothelial cells

  • Phytomedicine. 2025 May:140:156498. doi: 10.1016/j.phymed.2025.156498.
Ruo-Yu Shang 1,  Jia-Cai Yang 1,  Wen-Gang Hu 2,  Rong Xiao 3,  Dong-Sheng Hu 3,  Zhi-Chen Lin 3,  Song Li 3,  Nan-Nan Wang 3,  Yin Zheng 3,  Zhi-Hui Liu 1,  Yun-Xia Chen 1,  Min-Jie Wang 4,  Chao Wang 3,  Bo Jiang 5,  Guo-An Lin 3,  Xiao-Liang Li 6,  Xin-Zhi Shang 7,  Tian-Tian Yan 8,  Gao-Xing Luo 9,  Wei-Feng He 10
Affiliations

Affiliations

  • 1 State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Wound Repair and Tissue Regeneration, Chongqing 400038, China.
  • 2 Department of Plastic and Burn Surgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400038, China.
  • 3 Military Burn Center, the 990th Hospital of the Joint Logistic Support Force, Zhu Madian 463000, China.
  • 4 Military Service Office, the 988th Hospital of the Joint Logistic Support Force, Zheng Zhou 450007, China.
  • 5 Department of pathology, the 990th Hospital of the Joint Logistic Support Force, Zhu Madian 463000, China.
  • 6 Department of Burns, Zhengzhou First People's Hospital, Zhengzhou 450004, China.
  • 7 Military Burn Center, the 990th Hospital of the Joint Logistic Support Force, Zhu Madian 463000, China. Electronic address: [email protected].
  • 8 Military Burn Center, the 990th Hospital of the Joint Logistic Support Force, Zhu Madian 463000, China. Electronic address: [email protected].
  • 9 State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Wound Repair and Tissue Regeneration, Chongqing 400038, China. Electronic address: [email protected].
  • 10 State Key Laboratory of Trauma and Chemical Poisoning, Institute of Burn Research, First Affiliated Hospital of Army Medical University (Third Military Medical University), Chongqing 400038, China; Chongqing Key Laboratory for Wound Repair and Tissue Regeneration, Chongqing 400038, China. Electronic address: [email protected].
PMID: 40055124 DOI: 10.1016/j.phymed.2025.156498
Abstract

Background Hypertrophic scarring is an abnormal condition involving excessive fibroblast activation, aberrant extracellular matrix deposition, and persistent inflammation. Current treatments have limited efficacy and potential adverse effects, necessitating the development of new approaches. Purpose In this study, we investigated the effects of artesunate (ART) on hypertrophic scar (HS) formation and explored the underlying cellular and molecular mechanisms. Methods ART was local injected in rabbit ear HS model to study its effect on HS formation. Cell viability was assessed using the CCK8 assay. Cell proliferation and targeted protein expression were detected by flow cytometry, immunofluorescence and immunohistochemistry staining. Scratch assays were performed to evaluate cell migration, while western blotting analysis was used to detect changes in protein expression. Results Local injection of ART significantly reduced scar protrusion and thickness, improved the immune microenvironment, and attenuated Collagen deposition. ART suppressed fibroblast activation, endothelial-mesenchymal transition (EndMT), and angiogenesis in HS tissues. In vitro, ART inhibited TGF-β1-triggered fibroblasts activation and EndMT of human umbilical vein endothelial cells. Mechanistically, ART attenuated the activation of PI3K/Akt/mTOR and TGF-β/Smad pathways in both fibroblasts and human umbilical vein endothelial cells. Notably, the mTOR Activator 740 Y-P reversed the fibrosis-inhibiting effects of ART in vitro and in vivo, highlighting the critical and intriguing role of PI3K/Akt/mTOR signaling in mediating the effects of ART. Furthermore, we first uncovered a crosstalk between PI3K/Akt/mTOR and TGF-β/Smad pathways, wherein PI3K/Akt/mTOR inactivation by ART partially contributed to the inhibition of TGF-β/Smad signaling. Conclusion In addition to fibroblast activation, our findings first demonstrate that ART effectively mitigates HS formation by modulating the immune microenvironment and inhibiting EndMT and fibroblast activation. These results provide new perspectives into the development of HS and underscore the promising potential of ART as a therapeutic option for debilitating condition.

Keywords

Artesunate; Endothelial-mesenchymal transition; Hypertrophic scar; Myofibroblast; PI3K/AKT/mTOR; TGF-β/Smad.

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