Matrix metalloproteinases in intestinal fibrosis and fibrostenosing Crohn’s disease: Current evidence, mechanistic hypotheses, and translational challenges

Fibrostenosing complications in Crohn’s disease arise from mixed transmural remodeling that includes inflammation, fibrosis, and muscular hypertrophy/hyperplasia. Matrix metalloproteinases (MMPs) are implicated in extracellular matrix turnover and inflammatory remodeling, but their precise role in stricture evolution remains incompletely defined. We review current evidence (2020-2026) on MMP biology in intestinal fibrosis and fibrostenosing disease, emphasizing assay limitations, tissue-layer heterogeneity, and the predominance of cross-sectional rather than longitudinal human data. This review examines current evidence on MMP classification and substrate specificities, current evidence on cytokine–MMP interactions and proposed spatial and contextual patterns of remodeling, MMP contributions to fibrosis and smooth muscle cell proliferation, assay caveats and interpretation guardrails that distinguish expression from activity across gut layers, candidate biomarkers (such as PRO-C3/-C6 and fecal or serum MMP-9, which remain investigational), and emerging but unproven therapeutic strategies highlighting clinical trials and optimization strategies. We propose a state- and layer-aware conceptual framework to organize these findings, while acknowledging that the proposed states likely overlap and have not been prospectively validated. Despite recent advances, clinical trials of anti-MMP agents such as andecaliximab have yielded limited efficacy, likely attributable to challenges in timing, drug specificity, and outcome assessment. Candidate biomarkers and emerging therapeutic strategies remain investigational, and no MMP-directed approach has yet demonstrated clinical utility for routine fibrosis staging or stricture prevention. Future research directions should prioritize longitudinal human studies, mechanistic elucidation of how MMPs influence fibrosis and/or smooth muscle hyperplasia, improved linkage between tissue biology and imaging, fibrosis-specific endpoints, and rigorous validation before clinical trial translation can be justified.