Persistent Post-Inflammatory Matrix Stiffening Defines a Premalignant Mechanical Niche in Ulcerative Colitis-Associated Neoplasia

Wang, Z.; Xie, N.; Xu, B.; Wu, J.; Cheng, B.; Cheng, Y.; Shi, H.; Shu, Q.; Li, Y.; Liang, X.; Shi, A.; Peng, Y.; Qin, B.; Song, M.; Wang, K.; Liu, X.; Wang, J.; Li, L.; Liu, J.; Liu, N.; Xu, F.

doi:10.64898/2026.06.17.733043

bioRxiv · 10.64898/2026.06.17.733043

Persistent Post-Inflammatory Matrix Stiffening Defines a Premalignant Mechanical Niche in Ulcerative Colitis-Associated Neoplasia

Wang, Z.·Xie, N.·Xu, B.·Wu, J.·Cheng, B.·Cheng, Y.·Shi, H.·Shu, Q.·Li, Y.·Liang, X.·Shi, A.·Peng, Y.·Qin, B.·Song, M.·Wang, K.·Liu, X.·Wang, J.·Li, L.·Liu, J.·Liu, N.·Xu, F.

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Abstract

Patients with long-standing ulcerative colitis (UC) remain at risk for colorectal neoplasia even after overt inflammatory activity improves, suggesting that repaired mucosa may retain residual tissue-level abnormalities. Whether extracellular matrix remodeling leaves a persistent mechanical cue that contributes to early neoplastic remodeling is unknown. Here we identify post-inflammatory matrix stiffening as a premalignant mechanical niche in UC-associated neoplasia. In human colonic biopsies, collagen remodeling and atomic-force-microscopy-based mucosal stiffness increased from non-UC controls to UC and UC-associated dysplasia. A stiffness-associated transcriptional program was also enriched in histologically non-dysplastic mucosa from patients with UC-associated neoplasia. In mouse models, colonic stiffness increased along the colitis-to-tumorigenesis axis and remained elevated during apparent recovery, when epithelial permeability, junctional protein loss, crypt proliferation and nuclear {beta}-catenin accumulation persisted despite reduced disease activity. Stiffness-controlled intestinal epithelial cultures showed that stiff substrates were sufficient to disrupt ZO-1 organization and enhance {beta}-catenin redistribution, particularly under TNF- stimulation. Pharmacological matrix normalization with {beta}-aminopropionitrile partially restored barrier organization and attenuated early epithelial remodeling in vivo. Single-cell profiling identified a stiffness-associated MMP7-positive/YAP-active epithelial state that was enriched in collagen-rich regions and reduced after matrix softening. Inhibition of YAP or MMP7 attenuated stiffness-associated junctional disruption and {beta}-catenin redistribution. These findings suggest that inflammatory recovery and mechanical recovery can be uncoupled, and that persistent mucosal stiffening provides a tissue-level mechanism by which chronically injured UC mucosa may remain biologically vulnerable to premalignant epithelial remodeling.

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Wang, Z., Xie, N., Xu, B., Wu, J., Cheng, B., Cheng, Y., Shi, H., Shu, Q., Li, Y., Liang, X., Shi, A., Peng, Y., Qin, B., Song, M., Wang, K., Liu, X., Wang, J., Li, L., Liu, J., Liu, N., Xu, F.. 2026-06-19. Persistent Post-Inflammatory Matrix Stiffening Defines a Premalignant Mechanical Niche in Ulcerative Colitis-Associated Neoplasia. https://doi.org/10.64898/2026.06.17.733043

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