Radiation-sensitive circRNA promotes intestinal regeneration

Area of Science:

• Molecular Biology
• Gastroenterology
• Radiation Oncology

Background:

• The intestine is highly sensitive to ionizing radiation (IR), leading to radiation-induced intestinal injury (RIII), which significantly impacts patient quality of life.
• Current diagnostic biomarkers and treatments for RIII are limited, necessitating the identification of new therapeutic targets.
• Circular RNAs (circRNAs) are implicated in various diseases, but their role in radiation-induced intestinal injury is largely unexplored.

Purpose of the Study:

• To identify novel circular RNAs involved in radiation-induced intestinal injury.
• To investigate the function and mechanism of a specific intestine-specific circRNA, circDmbt1(3,4,5,6), in protecting against radiation damage.
• To evaluate circDmbt1(3,4,5,6) as a potential diagnostic biomarker and therapeutic target for RIII.

Main Methods:

• RNA sequencing was used to identify differentially expressed circRNAs.
• In vitro studies explored the effects of circDmbt1(3,4,5,6) on intestinal epithelial cells' proliferation, apoptosis, and DNA damage.
• Intestinal organoids and a mouse model were utilized to validate the role of circDmbt1(3,4,5,6) in radiation-induced intestinal injury.

Main Results:

• CircDmbt1(3,4,5,6) was downregulated in mouse intestines post-irradiation and correlated with injury severity.
• Overexpression of circDmbt1(3,4,5,6) promoted cell proliferation, reduced apoptosis and DNA damage, and enhanced organoid survival after radiation.
• In vivo, circDmbt1(3,4,5,6) overexpression improved intestinal length, epithelial integrity, and the proportion of key cell types, facilitating intestinal adaptation.

Conclusions:

• CircDmbt1(3,4,5,6) is a novel, rapidly responding biomarker for early-stage RIII.
• Exogenous expression of circDmbt1(3,4,5,6) enhances intestinal recovery following radiation damage.
• The circDmbt1(3,4,5,6)/miR-125a-5p/STAT3 axis is crucial for intestinal epithelial regeneration after radiation, presenting a potential diagnostic and therapeutic strategy for RIII.