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

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.