Inhibition of ferroptosis by microbiota‐derived lithocholic acid underlies the intestinal radioprotection of a host defensin‐derived oligopeptide

Abstract Ionizing radiation‐induced intestinal injury (IRIII) reduces survival in nuclear accident victims and compromises the efficacy of abdominal radiotherapy, and current treatment options remain limited. Human defensin 5 (HD5)‐derived fragments are endogenous regulators of the gut microbiota, which affects host responses to radiation. However, whether these fragments influence intestinal radiosensitivity or can serve as lead compounds for IRIII therapeutics remains unclear. In this study, we investigated the role of HD5‐derived fragments in IRIII and developed AT9(C/G), a potent radioprotective oligopeptide based on the lead fragment AT9. Fecal metagenomic and metabolomic analyses revealed that the oral administration of AT9(C/G) enriches Bifidobacterium pseudolongum and increases lithocholic acid (LCA) levels in the intestine. Both murine and clinical studies demonstrated a negative correlation between IRIII severity and fecal LCA levels. The radioprotective effect of LCA was further validated in both mouse models and human small intestinal organoids. Mechanistically, LCA suppresses ferroptosis in irradiated cells by remodeling lipid metabolism. Specifically, LCA activates Takeda G protein‐coupled receptor 5 (TGR5), leading to the upregulation of sterol regulatory element‐binding protein 1 (SREBP1), which transcriptionally modulates stearoyl‐CoA desaturase 1 (SCD1) to catalyze monounsaturated fatty acid production. Pharmacological inhibition of SCD1 or genetic ablation of G‐protein coupled bile acid receptor 1 ( Gpbar1 , encodes TGR5) attenuates the protective effects of AT9(C/G) in mice. This study establishes that an oligopeptide can modulate gut microbiota‐derived LCA to confer intestinal radioprotection, presenting a promising preventive strategy against IRIII.