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Upon activation, PSCs promote extracellular matrix (ECM) remodeling and increase tissue stiffness, which in turn reinforces PSC activation via nuclear localization of Yes\u2010associated protein (YAP), creating a self\u2010sustaining fibrotic loop that facilitates tumor progression. Given the limited success of CAF depletion strategies, we explored whether PSC activation could be reversed through mechanical reprogramming via force\u2010sensitive cadherin signaling. Here, we show a tunable polyethylene glycol (PEG)\u2010based hydrogel system functionalized with RGD and HAVDI peptides to simulate varying matrix stiffness and N\u2010cadherin ligation. We found that HAVDI\u2010mediated N\u2010cadherin ligation reduced the contractile state by disrupting the actin cap formation and nuclear flattening and thereby reducing\u00a0nuclear YAP localization in PSCs, at intermediate stiffness (10\u201320\u00a0kPa). Furthermore, HAVDI\u2010mediated reprogramming reversed PSC activation within a defined time window, suggesting that both matrix stiffness and mechanical dosing history critically determine reprogramming efficiency. Collectively, this study highlights a novel approach for CAFs reprogramming through mechanical modulation of cadherin signaling, offering new therapeutic potential in PDAC treatment.<\/jats:p>","DOI":"10.1002\/smtd.202501659","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T20:12:25Z","timestamp":1773000745000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["N\u2010cadherin Adhesive Interactions Mechanically Modulate Phenotype of Pancreatic Stellate Cells\u00a0via YAP\u2010dependent Mechanosensing"],"prefix":"10.1002","volume":"10","author":[{"given":"Simei","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Anesthesiology and Center for Brain Science The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. China"},{"name":"Department of Hepatobiliary Surgery The First Affiliated Hospital of Xi'an Jiaotong University  Xi'an P. R. 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