Nonanticoagulated Heparin Derivatives Mediate Goblet Cell Differentiation to Restore the Mucosal Barrier for Ulcerative Colitis Therapy

Hu, W.; Liu, Z.; Huang, L.; Zeng, W.; Ren, X.; Ji, Y.; Zhou, Q.; Xu, B.; Zhang, C. Y.; Zhang, C.; Zhang, Z. Q.; Zhang, H.; Yang, Y. S.; Chen, Y.; Jiang, X.; Wang, Y.; Xing, X.-H.

doi:10.64898/2026.02.12.705304

bioRxiv · 10.64898/2026.02.12.705304

Nonanticoagulated Heparin Derivatives Mediate Goblet Cell Differentiation to Restore the Mucosal Barrier for Ulcerative Colitis Therapy

Hu, W.·Liu, Z.·Huang, L.·Zeng, W.·Ren, X.·Ji, Y.·Zhou, Q.·Xu, B.·Zhang, C. Y.·Zhang, C.·Zhang, Z. Q.·Zhang, H.·Yang, Y. S.·Chen, Y.·Jiang, X.·Wang, Y.·Xing, X.-H.

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Abstract

Epithelial mucus barrier dysfunction is a pathological hallmark of ulcerative colitis (UC), yet current clinical therapeutic strategies primarily suppress inflammation, lacking reliable approaches for restoration of the mucosal layer. Here, through a systematic screen of our established library of deanticoagulated heparins, we identified NALHP, a non-anticoagulant low-molecular-weight heparin derivative, and its representative fraction S6 as orally active epithelial repair-promoting glycans. NALHP/S6 restored crypt architecture, mucus production and epithelial barrier integrity in experimental colitis. In UC patient-derived colonic organoids, NALHP/S6 reduced aberrant stem/proliferative programs while promoting secretory, absorptive and junctional maturation. Single-cell transcriptomics and temporal validation identified a transient repair-secretory transitional state (RSTS) positioned between classical Wnt-associated stemness and mature barrier-forming epithelial states. Transcriptomic analysis revealed coordinated attenuation of Wnt and Notch signaling, whereas pharmacological reactivation of these pathways opposed NALHP/S6-induced epithelial state progression. These findings define mucosal repair as a regulated epithelial-state transition and identify NALHP/S6 as glycan-based modulators capable of restoring this progression in UC epithelium.

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Hu, W., Liu, Z., Huang, L., Zeng, W., Ren, X., Ji, Y., Zhou, Q., Xu, B., Zhang, C. Y., Zhang, C., Zhang, Z. Q., Zhang, H., Yang, Y. S., Chen, Y., Jiang, X., Wang, Y., Xing, X.-H.. 2026-02-13. Nonanticoagulated Heparin Derivatives Mediate Goblet Cell Differentiation to Restore the Mucosal Barrier for Ulcerative Colitis Therapy. https://doi.org/10.64898/2026.02.12.705304

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