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Cell Physiol Biochem. 2018;48(3):959-970. doi: 10.1159/000491964. Epub 2018 Jul 23.

Metformin Alleviates Radiation-Induced Skin Fibrosis via the Downregulation of FOXO3.

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Department of Radiation Oncology, Yonsei University Health System, Seoul, Republic of Korea.
Department of Dermatology, Yonsei University Health System, Seoul, Seoul, Republic of Korea.
Radiation Epidemiology Team, Radiation Health Institute KHNP, Seongnam-si, Republic of Korea.
Department of Plastic Surgery, Yonsei University Health System, Seoul, Republic of Korea.
Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, Republic of Korea.



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.


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).


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.


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.


FOXO3; Metformin; PIK3r1; Radiation-induced skin fibrosis

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