Inhibition of keloid fibroblast proliferation by artesunate is mediated by targeting the IRE1α/ XBP1 signaling pathway and decreasing TGF-β1

Background: Keloid is a benign hyperplastic dermatosis with high recurrence rate and complex pathogenesis. There is no universally effective treatment yet. New therapies and elucidation of pathogenesis are urgently required. Aims: To explore the function of IRE1 alpha/XBP1 in keloid fibroblasts and to investigate the potential mechanism of artesunate in inhibiting keloid hyperplasia. Methods: Human keloid fibroblasts (KFs) were cultured, and the expressions of XBP1 and TGF-(31 were detected by immunohistochemistry. The expression of IRE1 was interfered with through cell transfection and the effects of IRE1 interference on cell proliferation and the cell cycle were assessed using MTS, colony formation assays, and flow cytometry. Detection of the expressions of XBP1 and TGF-(31 by qRT-PCR and Western blot. Then artesunate was applied to a subset of the cells, and its effects on cell viability and the expression of related proteins using the same methods. Results: The IRE1 alpha/XBP1 pathway was activated in KFs. Knocking out the gene IRE1 alpha can inhibit the expression of TGF-(31, in addition, the cell viability and cell cycle progression of KFs were also significantly affected. After artesunate treatment, there was a remarkable reduction in cell proliferation. Meanwhile, the cell cycle of KFs treated with artesunate was blocked in G1 phase.After upregulating the expression of IRE1 alpha and treating KFs with artesunate, both cell cycle and proliferation showed inhibitory effects, and related proteins also exhibited suppressed expression. Conclusions: The IRE1 alpha/XBP1 pathway is activated in keloid, and inhibiting the expression of this pathway can affect the cell proliferation activity. In addition, artesunate also has a significant effect on fibroblast proliferation, and the IRE1 alpha/XBP1 pathway may participate in this process. These findings suggest that IRE1 alpha/XBP1 signal pathway may be a potential target for scar treatment, and artesunate could also be a powerful candidate for keloid treatment. (c) 2024 Elsevier Ltd and ISBI. All rights reserved.