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

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 β-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 β-catenin redistribution, particularly under TNF-α stimulation. Pharmacological matrix normalization with β-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 β-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.