ORIGINAL RESEARCH article
Front. Cell Dev. Biol.
Sec. Molecular and Cellular Pathology
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1678654
IGF1R promotes radiation-induced HSCs activation by regulating DNA-PKcs-mediated DNA damage repair
Provisionally accepted
- Jilin University, Changchun, China
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Ionizing radiation (IR)-induced liver fibrosis is one of the most serious complications caused by radiotherapy for liver cancer, and the development core of the liver fibrosis is the activation of hepatic stellate cells (HSCs). Insulin like growth factor 1 receptor (IGF1R) is commonly known as a growth-promoting kinase receptor that has critical role in cell differentiation and tissue reorganization, as well as in promoting the activation of HSCs tentatively. Additionally, there has also been a resurgence of interest in its role in DNA damage repair, nevertheless the mechanism has been less well known. Considering that DNA damage and repair are the most serious radiation injury events, the aim of this study was to explore the mechanism of IGF1R in activation of HSCs by regulating DNA damage repair. Herein, we firstly confirmed that IR induced activation of HSCs along with DNA damage and the upregulation of DNA-dependent protein kinase (DNA-PKcs) and IGF1R expression. This indicated the radiation-induced activation of HSCs and DNA damage repair were promoted by activation or overexpression of IGF1R lonely or together with DNA-PKcs activation, mechanismly through IGF1R-DNA-PKcs interactions. The process is primarily facilitated by the nuclear translocation of IGF1R, which promotes PRKDC transcription at the mRNA level. Moreover, it involves an interaction with DNA-PKcs in the cytoplasm at the protein level, which in turn facilitates the entry of DNA-PKcs into the nucleus and subsequent promotion of DNA damage repair. Eventually, our findings suggest that inhibition of the IGF1R-promoted DNA-PKcs dependent NHEJ repair mode is a promising strategy to prevent activation of HSCs. As far as we known, the present study is pioneering in its exploration of the mechanism by which IGF1R mediates radiation-induced activation of HSCs through regulating DNA-PKcs.
Keywords: IGF1R, DNA damage repair, DNA-PKcs, Hepatic Stellate Cells, Ionizing radiation
Received: 03 Aug 2025; Accepted: 08 Oct 2025.
Copyright: © 2025 Lin, Zhao, Feng, Sun, Liu, Li, Shen and Cheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Yunyun Cheng, chengyy@jlu.edu.cn
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