sDR5-Fc Administered Post-Exposure Alleviates Radiation-Induced Enteric Injury by Inhibiting ROS and NLRP3/Caspase-1/GSDMD-Dependent Pyroptosis and Inflammatory Response

Background: The risk of ionizing radiation exposure, including accidents and medical complications, has increased with the rapid development and broad application of nuclear technology. The intestine is highly susceptible to radiation, with radiation-induced intestinal injury characterized by a complex cascade of cellular and molecular reactions. This cascade results in the death of intestinal epithelial cells, which compromises the integrity of the intestinal mucosal barrier and disrupts immune regulation. At present, there are several limitations in the research on the therapy of radiation-induced intestinal injury, including uncertain mechanisms and an absence of optimal pharmaceuticals. This study aims to explore the post-exposure treatment effects of sDR5-Fc (a DR5 antagonist) on radiation-induced intestinal pyroptosis damage. Methods: In this study, C57BL/6 mice, human HIEC-6, and rat IEC-6 intestinal epithelial cells were exposed to a single 15 Gy high-dose γ-irradiation to establish an acute radiation-induced intestinal injury model. All sDR5-Fc treatments were administered after radiation exposure to simulate clinical post-exposure intervention. In vivo histological staining was performed for quantitative evaluation of intestinal damage. In vitro cell viability and LDH release assays were used to evaluate intestinal epithelial injury. Multiple detection methods, including scanning electron microscopy (SEM), flow cytometry, peripheral blood routine analysis, organ index detection, immunohistochemistry, qRT-PCR, and Western blotting, were applied to assess radiation-induced alterations in oxidative stress (ROS, MDA) and pyroptosis-associated inflammasome indicators (NLRP3, caspase-1, GSDMD-N, IL-1β, IL-18). Results: It was observed that treatment with soluble DR5-Fc fusion protein (sDR5-Fc), a DR5 antagonist, markedly reduced these radiation-induced effects. Mice subjected to 15 Gy total abdominal γ-irradiation exhibited similar outcomes after sDR5-Fc administration, including inhibited pyroptosis in intestinal and colonic tissues, enhanced recovery of peripheral blood cells (leukocytes, erythrocytes, and platelets), improved organ indices of the spleen and thymus, and an increased 30-day survival rate. Histological examination and pathological scoring confirmed significant structural damage in the irradiated group, and these pathological alterations were partially reversed following sDR5-Fc administration. Molecular docking and BLI assays suggest a potential in vitro interaction between DR5 and NLRP3, which can be interfered with by sDR5-Fc. Moreover, qRT-PCR and Western blotting assays indicated that sDR5-Fc attenuated pyroptosis by reducing the NLRP3/caspase-1/GSDMD signaling pathway. Conclusions: These findings suggest that sDR5-Fc, as a DR5 antagonist, is a promising therapeutic candidate for mitigating high-dose radiation-induced intestinal injury; however, further research is warranted.