Citraconic acid mitigates radiation-induced intestinal injury by modulating IL-17 signaling to enhance epithelial regeneration.

OBJECTIVE

This study investigates the protective effects of citraconic acid (CA) on radiation-induced intestinal injury (RIII) and elucidates its relationship with the interleukin-17 (IL-17) signaling pathway.

METHODS

A mouse model of whole-abdominal irradiation (IR) was established, and CA (10, 20, 40 mg/kg) was administered intraperitoneally as an intervention. Assessments included body weight, Disease Activity Index (DAI), and colon length measurements. Serum and tissue inflammatory markers were quantified using enzyme-linked immunosorbent assay. Histological analysis was performed using Hematoxylin and Eosin (HE) staining, Ki67 and Lgr5 immunohistochemistry, Alcian Blue-Periodic Acid-Schiff (AB-PAS) staining, and immunofluorescence for Zonula Occludens-1 (ZO-1) and Occludin. Transcriptomic sequencing with functional enrichment analyses was conducted, followed by Western blot validation of IL-17 A, CCL7, CXCL2, and MMP13 protein expression. IL-17 inhibitor experiments were performed to validate the causal relationship.

RESULTS

CA administration attenuated body weight loss and reduced DAI scores in a dose-dependent manner while preserving colon length. CA treatment suppressed the elevation of IL-6 and TNF-α levels induced by irradiation. Furthermore, CA enhanced the abundance of Ki67-positive and Lgr5-positive cells, increased goblet cell numbers and mucus secretion, and restored the expression of tight junction proteins ZO-1 and Occludin, thereby improving histological damage. Transcriptomic analysis revealed significant enrichment of IL-17 signaling pathways associated with regeneration and inflammation. Protein levels of IL-17 A, CCL7, CXCL2, and MMP13 were upregulated following CA treatment. Importantly, IL-17 inhibition abolished the protective effects of CA, confirming the dependence on IL-17 signaling.

CONCLUSION

CA exerts protective effects against radiation-induced intestinal injury by modulating the IL-17-related signaling network, thereby promoting intestinal epithelial regeneration and barrier repair. These findings suggest that CA may represent a potential metabolic intervention strategy for the prevention and treatment of radiation-induced gastrointestinal damage.