FLASH radiotherapy drives intestinal regeneration via macrophage-derived WNT4 signaling and attenuated T-cell inflammation

Whole-abdominal FLASH radiotherapy in mice preserves Lgr5+ stem cells and Fabp1+ absorptive epithelium, with day-3 repair linked to macrophage-enriched WNT4 signaling and early transient {beta}-catenin activation.

• Why it matters: Dose-rate–dependent mechanisms behind improved intestinal repair after FLASH-RT are unclear, especially how regenerative programs and immune inflammation are coordinated during recovery.
• What they did: Mice received whole-abdominal FLASH-RT or CONV-RT, then single-cell transcriptomics, trajectory analysis, cell-cell communication inference, and in vivo Wnt4 pathway perturbations were used to map the repair ecosystem.
• The result: FLASH enriched Mrc1 macrophages and increased WNT4-associated signaling involving Fzd5Lrp5/6-expressing stem cells, while Wnt4 augmentation promoted crypt regeneration after CONV-RT and FLASH reduced Tcf7/Tbx21 CD4 T cells and TNF.

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