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We established a prospective cohort integrating stromal biobanking, functional phenotyping, cross-cohort benchmarking, and outcome modeling to define disease-anchored cellular states. Colonic myofibroblasts from 34 individuals spanning health, ulcerative colitis, and Crohn\u2019s disease resolved into\n                  <jats:bold>two dominant states<\/jats:bold>\n                  : inflammatory (\n                  <jats:bold>IMFs<\/jats:bold>\n                  ) and quiescent (\n                  <jats:bold>QMFs<\/jats:bold>\n                  ) myofibroblasts. QMF predominance forecasted remission, whereas IMF predominance increased the odds of worsening endoscopic severity despite therapy escalation during follow-up by \u223c4.6-fold, linking early stromal biology to clinical outcomes. Unlike QMFs, IMFs exhibited a senescence-associated secretory phenotype that impaired epithelial stemness, barrier integrity, and innate immune fitness. State-guided prioritization identified EDNRB-antagonism as a high-confidence stromal intervention, reversing pathogenic phenotypes across orthogonal assays and species. Outcome simulation positioned stromal-state reversibility by EDNRB-antagonism as a precision axis, reducing odds of recalcitrance by \u223c96.4% and reframing treatment resistance as a reversible stromal state.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Graphic Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"720931v2_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                  <jats:p>\n                    In this work, Tindle\n                    <jats:italic>et al.<\/jats:italic>\n                    identify reversible stromal states that govern remission vs. recalcitrant outcomes in IBD and nominate precision reprogramming of pathogenic myofibroblasts as a new therapeutic strategy.\n                  <\/jats:p>\n       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