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Background <p>The intestine is one of the most sensitive organs to ionizing radiation&#xa0;(IR), and radiation-induced intestinal injury (RIII) impacts the quality of life of patients undergoing radiotherapy. There are limited early diagnostic biomarkers and specific medicines clinically approved for RIII. Therefore, we sought to identify new theranostic targets to prevent RIII and to facilitate the reestablishment of the intestinal epithelium. Circular RNAs (circRNAs) are widely appreciated as pervasive regulators of many diseases and multiple biological processes, while whether and how specific circRNAs are involved in radiation-induced intestinal injury remains largely unknown.</p> Methods <p>Differentially expressed circRNAs were analyzed and verified via RNA sequencing. The function of an intestine-specific circRNA (termed <i>circDmbt1(3,4,5,6)</i>) on cell proliferation, apoptosis, and DNA damage level after radiation was explored in&#xa0;vitro, and the underlying mechanism was further investigated. Ultimately, intestinal organoids and mice model were used to verify the role of <i>circDmbt1</i><i>(3,4,5,6)</i> on radiation-induced intestinal injury.</p> Results <p>Primarily expressed in intestinal stem cells, <i>CircDmbt1(3,4,5,6)</i> was downregulated in mice intestines after 14&#xa0;Gy abdominal radiation and showed timely relationship with intestinal injury level. <i>CircDmbt1(3,4,5,6)</i> promoted the proliferation and alleviated cell apoptosis and DNA damage level of intestinal epithelial cells and promoted organoids survival after radiation compared with control groups. In&#xa0;vivo experiments showed that compared with control groups, overexpression of <i>circDmbt1(3,4,5,6)</i> could increase intestinal length; enhance epithelial integrity and the percentage of proliferative cells, stem cells, paneth cells, and goblet cells; and promote intestinal adaption after radiation. Mechanistically, <i>circDmbt1(3,4,5,6)</i> protects intestines from IR via <i>circDmbt1(3,4,5,6)</i>/miR-125a-5p/STAT3.</p> Conclusions <p><i>CircDmbt1(3,4,5,6)</i>, a novel promising RIII bio-marker, responses rapidly at the early stage after 14&#xa0;Gy abdominal irradiation, and exogenous expression of <i>circDmbt1(3,4,5,6)</i> could promote intestinal fitness in RIII. We reveal that the <i>circDmbt1(3,4,5,6)</i>/miR-125a-5p/STAT3 axis is important to the regeneration of the intestinal epithelium after radiation-induced damage, providing a potential diagnostic and therapeutic target for RIII.</p> Graphical abstract <p></p>

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Radiation-sensitive circRNA promotes intestinal regeneration

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月29日

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  • Hui Cai,
  • Xin Liang,
  • Shazhen Ai,
  • Hao Sun,
  • Xinyu Zhang,
  • Qianying Lu,
  • Qingshan Yang,
  • Ying Li,
  • Di Zhao,
  • Manman Zhang,
  • Kaihua Ji,
  • Yan Wang,
  • Qiang Liu

摘要

Background

The intestine is one of the most sensitive organs to ionizing radiation (IR), and radiation-induced intestinal injury (RIII) impacts the quality of life of patients undergoing radiotherapy. There are limited early diagnostic biomarkers and specific medicines clinically approved for RIII. Therefore, we sought to identify new theranostic targets to prevent RIII and to facilitate the reestablishment of the intestinal epithelium. Circular RNAs (circRNAs) are widely appreciated as pervasive regulators of many diseases and multiple biological processes, while whether and how specific circRNAs are involved in radiation-induced intestinal injury remains largely unknown.

Methods

Differentially expressed circRNAs were analyzed and verified via RNA sequencing. The function of an intestine-specific circRNA (termed circDmbt1(3,4,5,6)) on cell proliferation, apoptosis, and DNA damage level after radiation was explored in vitro, and the underlying mechanism was further investigated. Ultimately, intestinal organoids and mice model were used to verify the role of circDmbt1(3,4,5,6) on radiation-induced intestinal injury.

Results

Primarily expressed in intestinal stem cells, CircDmbt1(3,4,5,6) was downregulated in mice intestines after 14 Gy abdominal radiation and showed timely relationship with intestinal injury level. CircDmbt1(3,4,5,6) promoted the proliferation and alleviated cell apoptosis and DNA damage level of intestinal epithelial cells and promoted organoids survival after radiation compared with control groups. In vivo experiments showed that compared with control groups, overexpression of circDmbt1(3,4,5,6) could increase intestinal length; enhance epithelial integrity and the percentage of proliferative cells, stem cells, paneth cells, and goblet cells; and promote intestinal adaption after radiation. Mechanistically, circDmbt1(3,4,5,6) protects intestines from IR via circDmbt1(3,4,5,6)/miR-125a-5p/STAT3.

Conclusions

CircDmbt1(3,4,5,6), a novel promising RIII bio-marker, responses rapidly at the early stage after 14 Gy abdominal irradiation, and exogenous expression of circDmbt1(3,4,5,6) could promote intestinal fitness in RIII. We reveal that the circDmbt1(3,4,5,6)/miR-125a-5p/STAT3 axis is important to the regeneration of the intestinal epithelium after radiation-induced damage, providing a potential diagnostic and therapeutic target for RIII.

Graphical abstract