{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T01:54:46Z","timestamp":1788400486433,"version":"build-2803163510"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T00:00:00Z","timestamp":1759881600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p> Proton pump inhibitors (PPIs) are widely prescribed for gastrointestinal disorders and are often used empirically in patients with pancreatic disease, yet their long-term impact on pancreatic health remains unclear. We evaluated whether regular PPI use is associated with risks of acute pancreatitis (AP), chronic pancreatitis (CP), and pancreatic cancer (PC).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We analyzed 489,394 UK Biobank participants aged 38\u201373 years, comparing regular PPI users with non-users and with histamine-2 receptor antagonist (H<jats:sub>2<\/jats:sub>RA) users as an active comparator. Associations with incident pancreatic outcomes were estimated using Cox regression models, landmark analysis, and propensity score matching, supplemented by multiple sensitivity analyses, including stratified\/interaction analyses, E-values, time-varying exposure models with immortal-time correction, dfbeta residuals correction, stricter follow-up with Firth penalization, full-cohort multivariable modeling, and alternative matching (disease risk score 1:1, entropy balancing). Complementary <jats:italic>in vivo<\/jats:italic> experiments used a cerulein-induced acute pancreatitis mouse model to examine the effects of short- and long-term PPI administration on pancreatic inflammation and histopathology.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In primary analyses, regular PPI use showed a time-dependent association with acute pancreatitis. However, this association was not robust: multiple sensitivity analyses indicated instability of the finding. Experimental validation in mice demonstrated that neither short-term nor long-term PPI administration altered pancreatic inflammation or histopathological damage in the cerulein-induced model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Integrating large-scale cohort data with experimental evidence, our findings suggest that regular PPI use does not meaningfully influence the risk of acute pancreatitis, chronic pancreatitis, or pancreatic cancer.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1673200","type":"journal-article","created":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T04:17:15Z","timestamp":1759897035000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Proton pump inhibitor use and pancreatic risk: evidence from the UK biobank participants and animal experiments"],"prefix":"10.3389","volume":"16","author":[{"given":"Xin","family":"Gao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zouhua","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingxie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenchen","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaowu","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingtian","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keyan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guotao","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiming","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengfeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaodong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1136\/gutjnl-2021-325097","article-title":"Proton pump inhibitors and risk of gastric cancer: population-based cohort study","volume":"71","author":"Abrahami","year":"2022","journal-title":"Gut"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1100","DOI":"10.1214\/aos\/1176345976","article-title":"Cox's regression model for counting processes: a large sample study","volume":"10","author":"Andersen","year":"1982","journal-title":"Ann. 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