Metrnl in mitigating radiation enteritis via label-retaining cells protection by modulating the c-KIT-WNT pathway.

Currently, there exists no definitive standardized therapy for radiation enteritis. This study unveils Metrnl as a pivotal regulator of intestinal radioprotection through multi-dimensional single-cell profiling and mechanistic dissection. We first demonstrate that radiation dynamically reprograms Metrnl expression in a time-dependent manner, revealing its role as a radiation-responsive mediator. Crucially, Metrnl confers potent protection against radiation-induced intestinal injury through double mechanisms; Metrnl safeguards label-retaining cells (LRCs) rather than conventional Lgr5+ intestinal stem cells, and activates a novel c-KIT-WNT signaling axis via ERK/GSK3β-mediated pathway crosstalk, both revitalizing intestinal epithelial regeneration. Therapeutically, recombinant Metrnl emerges as a potential biotherapeutic, effectively attenuating radiation enteritis. These findings establish Metrnl as a key mediator bridging radiation biology and regenerative medicine, offering a transformative potential for radiation injury management.