{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:05:14Z","timestamp":1790661914294,"version":"4.1.0"},"reference-count":40,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"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. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Fluoropyrimidines, including 5-fluorouracil (5-FU), capecitabine, tegafur, and trifluridine, are widely used anticancer agents, but their gastrointestinal toxicities remain clinically important. This study characterized fluoropyrimidine-associated adverse-event reporting signals across multiple pharmacovigilance databases and described epithelial-cell responses that may provide experimental context for gastrointestinal toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Adverse-event reports from the US Food and Drug Administration Adverse Event Reporting System (FAERS), Japanese Adverse Drug Event Report database (JADER), and Canada Vigilance Adverse Reaction Database (CVARD) were analyzed using the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPNN), and empirical Bayes geometric mean (EBGM) approaches. Time to onset (TTO) analysis was limited to FAERS because complete onset information was unavailable in JADER and CVARD. GES-1 gastric epithelial cells and NCM460 colonic epithelial cells were used for acute and 7-day repeated-exposure injury experiments. Additional representative-treatment experiments assessed fluorescein isothiocyanate (FITC)-dextran permeability and relative supernatant interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-\u03b1) levels.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Fluoropyrimidines showed gastrointestinal reporting signals with drug-specific reporting patterns. TTO analysis in FAERS showed an overall early-reporting pattern; the distribution of reports between days 181 and 360 was exploratory.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , fluoropyrimidines reduced epithelial viability, increased lactate dehydrogenase (LDH) release and reactive oxygen species (ROS) accumulation and decreased the JC-1 red\/green ratio. Epithelial injury was also observed under the 7-day repeated-exposure conditions. Quantitative real-time polymerase chain reaction (qPCR) showed lower\n                      <jats:italic>TJP1, OCLN<\/jats:italic>\n                      , and\n                      <jats:italic>CDH1<\/jats:italic>\n                      transcript abundance and increased expression of selected epithelial inflammatory-response and extracellular-matrix-remodeling genes. In the functional assays, FITC-dextran permeability and relative supernatant IL-6 and TNF-\u03b1 levels increased after 5-FU, capecitabine, and trifluridine exposure.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study identifies pharmacovigilance reporting signals and provides experimental evidence that fluoropyrimidine exposure is associated with epithelial injury, impaired barrier function, and epithelial inflammatory responses. The reporting signals do not estimate event frequency in treated populations or establish causality and require confirmation in exposure-adjusted studies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1934652","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:50:31Z","timestamp":1790661031000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Fluoropyrimidine-associated gastrointestinal toxicity: pharmacovigilance reporting signals and in vitro evidence of epithelial injury, barrier impairment, and inflammatory responses"],"prefix":"10.3389","volume":"17","author":[{"given":"Xinchi","family":"Luan","sequence":"first","affiliation":[{"name":"Department of Oncology, The Affiliated Hospital of Qingdao University","place":["Qingdao, Shandong, 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