Abstract
Cell polarity is essential for maintaining intestinal epithelial organization and function. Here we show that combined loss of polarity by epithelial loss of Cdc42 with oncogenic Kras expression in mice causes small intestine failure leading to weight loss, inflammation, epithelial necroptosis, and lethality. These phenotypic defects are characterized by a loss of intestinal stem cells, disrupted epithelial architecture, altered hippo signaling, elevated inflammatory cytokines, and activation of necroptotic cell death, that closely resemble necrotizing enterocolitis (NEC). Single-cell transcriptomic analysis reveals a coordinated dysregulation of polarity machinery, inflammatory pathways, and necroptosis program. Suppression of YAP, IL-1, TNFα signaling or necroptosis rescues the intestinal pathology. Similar NEC-like phenotypes arise when Cdc42 loss and oncogenic Kras activation are initiated from intestinal stem cells. These findings provide mechanism insights involving polarity-YAP-IL1/TNFα signaling induced necroptosis for the synergistic effect of hyperactivation of Kras signaling and loss of polarity in disrupting intestinal epithelia.
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All data are included in the Supplementary Information or available from the authors, as are unique reagents used in this Article. The raw numbers for charts and graphs are available in the Source Data file whenever possible. Source data are provided with this paper. The scRNA-seq data generated in this study were deposited at the Gene Expression Omnibus (RRID:SCR_005012) under accession number GSE294390 (GSM8903735, GSM8903736, GSM8903737, GSM8903738). The hyperlinks for these data are. GSE294390(study). GSM8903735(WT). GSM8903736(CDC42 KO). GSM8903737(Kras). GSM8903738(CDC42 KO/Kras Source data are provided with this paper.
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Acknowledgments
We thank the Cincinnati Children’s Hospital Medical Center Discover Together Biobank for support of this study, as well as participants and their families, whose help and participation made this work possible. We thank the expert technical support of James F. Johnson. This work was partly supported by NIH P30 DK078392 (L.D.), NIH U54 DK126108 (Y.Z.), NIH R01 AG063967 (Y.Z.), and NIH R01 CA278756 (Y.Z.).
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Z.Z. conceived the project, designed experiments, performed experiments, carried out data analyses and interpretation, and wrote the paper with input from the rest of the authors. C.F. performed the flow cytometry study. R.J. assisted in performing experiments and manuscript preparation. P.S. provided human NEC samples for analysis. M.A. performed bioinformatic analysis on the single-cell RNAseq data. Y.Z. provided overall supervision of the study, conceived the project, designed experiments, and wrote the paper.
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Zhang, Z., Fan, C., Jorgensen, R. et al. Loss of polarity by Cdc42 depletion and oncogenic Kras activation in the mouse intestinal epithelia leads to a necrotizing enterocolitis (NEC)-like disease. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70677-9
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DOI: https://doi.org/10.1038/s41467-026-70677-9
