The synthetic estradiol analog E0703 enhances Akkermansia muciniphila growth for radiation‐induced intestinal damage repair

Abstract The development of safe and effective radioprotective agents with minimal side effects, particularly for high‐dose exposure, remains a global priority. E0703, a novel steroidal compound structurally derived from estradiol, has shown promising radioprotective efficacy with limited estrogenic activity in prior pharmacodynamic studies. In this study, E0703 was found to significantly increase the abundance of Akkermansia muciniphila (AKK) in the intestines of both irradiated and non‐irradiated mice. Co‐administration of E0703 and AKK markedly improved the 7‐day survival rate of mice exposed to a lethal 8.5 Gy dose of radiation. E0703 induced beneficial transcriptional changes in AKK, with enrichment in metabolic pathways such as amino acid biosynthesis, aminoacyl‐tRNA biosynthesis, the tricarboxylic acid (TCA) cycle, and fatty acid biosynthesis. These alterations supported the production of glucosamine 6‐phosphate (GlcN‐6‐P) by AKK, which contributed to intestinal tissue regeneration following irradiation. Single‐cell transcriptomic analysis revealed that E0703 significantly increased the proportion of intestinal stem cells and goblet cells by Day 5 post irradiation. Mechanistically, E0703 modulated the oxidative phosphorylation pathway in these cell types, including regulation of Muc2 production. E0703 also enhanced AKK abundance in irradiated mice, particularly in the presence of mucin, thereby elevating the availability of GlcN‐6‐P—a critical substrate for intestinal organoid repair. These findings indicate that E0703 exerts direct effects on goblet cells and AKK, promoting host–microbe interactions that facilitate intestinal regeneration and improve survival following radiation exposure.