Background/Aims: Radiation-induced skin fibrosis is a common side effect of clinical radiotherapy. Our previous next-generation sequencing (NGS) study demonstrated the reduced expression of the regulatory α subunit of phosphatidylinositol 3-kinase (PIK3r1) in irradiated murine skin. Metformin has been reported to target the PIK3-FOXO3 pathway. In this study, we investigated the effects of metformin on radiation-induced skin fibrosis. Methods: Metformin was orally administered to irradiated mice. Skin fibrosis was analyzed by staining with H&E and Masson's trichrome stain. The levels of cytokines and chemokines associated with fibrosis were analyzed by immunohistochemistry and quantitative RT-PCR. The roles of PIK3rl and FOXO3 in radiation-induced skin fibrosis were studied by overexpressing PIK3rl and transfecting FOXO3 siRNA in NIH3T3 cells and mouse-derived dermal fibroblasts (MDF). Results: The oral administration of metformin significantly reduced radiation-induced skin thickening and collagen accumulation and significantly reduced the radiation-induced expression of FOXO3 in murine skin. Additionally, the overexpression of PIK3r1 reduced the radiation-induced expression of FOXO3, while FOXO3 silencing decreased the radiation-induced expression of TGFβ in vitro. Conclusions: The results indicated that metformin suppresses radiation-induced skin injuries by modulating the expression of FOXO3 through PIK3r1. Collectively, the data obtained in this study suggested that metformin could be a potent therapeutic agent for alleviating radiation-induced skin fibrosis.
Bibliographical noteFunding Information:
This study was supported by a grant from the ? orea Institute of Radiological and ?edical Sciences (?IRA?S), funded by ?inistry of Science ICT (?SIT), Republic of ? orea ( 猃礃猃猃爃瘃眃眃眃礁 猃礃猃猃爃瘃眃眃甃稁 猃礃猃猃爃瘃眃眃眃瘂thIe. TRhade iasttuiodny was also funded by Technology Research and Development Program (NRF-球爃猃礀ဃ琀A 琀A 礀A 爃球爃猃笃砃猃琁 球爃猃眀ဃ琀A 琀A 礀A 爃甃爃瘃瘃稃甃猂I, and the Basic Science Research Program (NRF-球爃猃砀R 猀A 砀A 甀A 猃猃笃甃球球球码 球爃猃礀R 猀D 猀A 猀B 爃甃爃球礃稃稃猂I through the National Foundation of ? orea, funded by the ?inistry of Education, by the Convergence of Conventional ?edicine and Traditional ? orean ?edicine R&D program funded by the ?inistry of Health & Welfare through the ? orea Health Industry Development Institute (HI 猃眀C 爃球猃瘂I. Also, a faculty research grant from the Yonsei University College of ?edicine ( 码球爃猃码爃猃眃稂I supported the study.
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