Abstract

Radiation-induced intestinal injury (RIII) is a serious and common complication of radiotherapy, and there are currently no effective therapeutic strategies. This study investigates the protective role of 4-octyl itaconate (4-OI), a cell-permeable itaconate derivative, against RIII. In vitro , 4-OI pretreatment enhanced the viability of irradiated intestinal epithelial cells, reduced reactive oxygen species (ROS) accumulation, and alleviated DNA damage. In a murine model of total body irradiation, 4-OI administration mitigated intestinal structural disruption, promoted crypt stem cell regeneration, and suppressed epithelial apoptosis. Mechanistically, 4-OI exerted its cytoprotective effects by modulating the SLC7A11/GPX4 axis to inhibit ferroptosis and enhancing glutathione biosynthesis. Furthermore, 16S rRNA sequencing revealed that 4-OI treatment recalibrated radiation-induced gut microbiota dysbiosis, suggesting an additional microbiome-mediated protective pathway. To our knowledge, the results represent the first demonstration of 4-OI's protective effects in RIII pathogenesis, positioning it as a novel therapeutic candidate for clinical radioprotection through dual mechanism targeting.