AUTHOR=Gao Xin , Xu Zouhua , Liu Qingxie , Yuan Chenchen , Dong Xiaowu , Shi Xiaolei , Zhu Qingtian , Wu Keyan , Xu Hongwei , Pan Jiajia , Lu Guotao , Xiao Weiming , Wang Shengfeng , Wang Yaodong 

TITLE=Proton pump inhibitor use and pancreatic risk: evidence from the UK biobank participants and animal experiments

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 16 - 2025

YEAR=2025

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1673200

DOI=10.3389/fphar.2025.1673200

ISSN=1663-9812

ABSTRACT=Introduction 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).MethodsWe analyzed 489,394 UK Biobank participants aged 38–73 years, comparing regular PPI users with non-users and with histamine-2 receptor antagonist (H2RA) 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 in vivo 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.ResultsIn 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.DiscussionIntegrating 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.