Ferrostatin-1 mitigates ionizing radiation-induced intestinal injuries by inhibiting apoptosis and ferroptosis: an in vitro and in vivo study

Intestinal injuries caused by ionizing radiation (IR) are a major complication of radiotherapy. Ferrostatin-1 (Fer-1) exerts antioxidant and anti-inflammatory effects. We investigated the influence of Fer-1 on IR-induced intestinal damage and explored the possible mechanisms.IEC-6 cells were administrated with Fer-1 for 30 min and subsequently subjected to 9.0 Gy-irradiation. Flow cytometry, qPCR, and WB were used to detect changes. For in vivo experiments, Fer-1 was given intraperitoneally to mice at 1 h before and 24 h after 9.0 Gy total body irradiation (TBI) respectively. Three days after TBI, the small intestines were isolated for analysis. The diversity and composition of the gut microbiota were analyzed by 16S rRNA gene sequencing.In vitro, Fer-1 protected IEC-6 cells from IR injury by reducing the production of ROS and inhibiting both ferroptosis and apoptosis. In vivo, Fer-1 enhanced the survival rates of mice subjected to lethal doses of IR and restored intestinal structure and physiological function. Further investigation showed that Fer-1 protected IEC-6 cells and mice by inhibiting the p53-mediated apoptosis signaling pathway and restoring the gut-microbe balance.This study confirms that Fer-1 protects intestinal injuries through suppressing apoptosis and ferroptosis.