{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T07:45:22Z","timestamp":1775979922736,"version":"3.50.1"},"posted":{"date-parts":[[2025,5,28]]},"group-title":"Pathology","reference-count":86,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T00:00:00Z","timestamp":1748390400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Pancreatitis is a potentially fatal and difficult to control exocrine-tissue defect with no FDA approved therapies. Variants of a chloride\/bicarbonate transporter cystic fibrosis transmembrane conductance regulator (CFTR) pose multi-fold increased risk of pancreatitis accounting for up to 40% of the patients with idiopathic pancreatitis. However, the relationship between the duct-restricted CFTR-function and total exocrine tissue defect during pancreatitis remains less known and animal models do not translate well to human disease. To overcome this challenge, we developed a robust and highly durable iPSC-derived model system of pancreatic ductal tissues from an idiopathic pancreatitis patient with a common pancreatitis-associated\n                  <jats:italic>CFTR<\/jats:italic>\n                  variant. In the patient line termed PANx, we found deficient CFTR function and a distinct gene expression signature for ductal tissue pancreatitis marked by aberrant mucin production, inflammatory cytokines and cystic neoplasms. By applying clinically used CFTR-modulator drug ivacaftor, we observed a remarkable restoration of deficient CFTR-mediated fluid secretion as well as upto 40% reversal of the differential gene signature for PANx including the reduction in mucinous neoplasms and immunogenic cytokines such as IL-11, CCL20 and CXCL8. We further employed a microsystem device to model hyperamylasemia, a diagnostic feature of acute pancreatitis attack, due to a ductal reaction causing acinar injury. The key mucinous signature was validated in primary pancreatitis ductal tissues with a\n                  <jats:italic>CFTR<\/jats:italic>\n                  variant. Overall, we unraveled new layers of CFTR-related pathology in pancreatitis to help us better understand the early course of this debilitating condition. The test methods and model systems discovered in this study will significantly expedite the discovery of diagnostic and therapeutic tools for treating idiopathic pancreatitis. For the first time, we provided molecular and physiologic evidence supporting the benefit of CFTR modulator drug ivacaftor in human CFTR-related pancreatitis.\n                <\/jats:p>","DOI":"10.1101\/2025.05.25.656006","type":"posted-content","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T03:30:19Z","timestamp":1748489419000},"source":"Crossref","is-referenced-by-count":0,"title":["Differential Expression and Microsystem Physiology Reveal Predominant and Drug Reversible CFTR-Related Defects in Idiopathic Pancreatitis"],"prefix":"10.64898","author":[{"given":"Paba","family":"Edisuriya","sequence":"first","affiliation":[{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, 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Critical Care Medicine, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hongyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Biomedical Data Science Shared Resource, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicholas","family":"Tatonetti","sequence":"additional","affiliation":[{"name":"Biomedical Data Science Shared Resource, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"},{"name":"Department of Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Danielle","family":"Hutchings","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alvin J.","family":"Freeman","sequence":"additional","affiliation":[{"name":"Nationwide Children\u2019s Hospital, The Ohio State University, College of Medicine, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaimie D.","family":"Nathan","sequence":"additional","affiliation":[{"name":"Nationwide Children\u2019s Hospital, The Ohio State University, College of Medicine, Columbus, OH 43205, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Appakalai N.","family":"Balamurugan","sequence":"additional","affiliation":[{"name":"Wendy Novak Diabetes Institute, Norton Children\u2019s Research Institute, Norton Healthcare, Division of Endocrinology, Department of Pediatrics, Pediatric Research Institute, University of Louisville, Louisville, KY, 40202, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephen 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