{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T07:45:21Z","timestamp":1791791121825,"version":"4.3.4"},"reference-count":52,"publisher":"Wiley","issue":"18","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2026,9,30]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Pancreatic ductal adenocarcinoma (PDAC) exhibits profound therapeutic resistance due to redox adaptation, particularly through Nrf2\/HO\u20101 pathway activation. Ferroptosis induction via GPX4 inhibitors (e.g., RSL3) is promising but limited by adaptive antioxidant responses. Ellagic acid (EA), a natural polyphenol, may overcome this resistance, yet its role in modulating ferroptosis remains unexplored.\n                    <jats:italic>In vitro<\/jats:italic>\n                    studies used KRAS\u2010mutant\u00a0and KRAS wild\u2010type PDAC cell lines (PANC\u20101, BxPC\u20103) treated with EA, RSL3, or both. Ferroptosis markers (iron, lipid ROS, MDA, GPX4), viability assays, and pathway analyses (Keap1\/Nrf2\/HO\u20101, p38 MAPK) were evaluated. In\u00a0vivo, antitumor efficacy was assessed in PANC\u20101 xenografts. EA synergized with RSL3, reducing viability in PDAC cells (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001) and suppressing tumor growth in\u00a0vivo (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.001). Combination therapy amplified ferroptotic markers as increased intracellular iron, MDA, and lipid ROS, versus RSL3 alone, while GPX4 expression decreased. Ferroptosis specificity was confirmed via Fer\u20101 rescue. Mechanistically, EA activated p38 MAPK, suppressing Nrf2 nuclear translocation and HO\u20101 expression. Keap1 upregulation further enhanced Nrf2 degradation. In\u00a0vivo, EA\u2009+\u2009RSL3 downregulated Nrf2\/HO\u20101 and elevated phospho\u2010p38 in tumors along with the induction of ferroptosis. EA potentiates RSL3\u2010induced ferroptosis in PDAC by disrupting the p38\/Nrf2\/HO\u20101 axis and elevating Keap1. This natural compound\u2010based strategy overcomes redox\u2010driven resistance, offering a translatable approach for PDAC models.\n                  <\/jats:p>","DOI":"10.1096\/fj.202602231r","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T11:06:56Z","timestamp":1789729616000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ellagic Acid Enhances\n                    <scp>RSL3<\/scp>\n                    \u2010Induced Ferroptosis by Inhibiting the Nrf2\/\n                    <scp>HO<\/scp>\n                    \u20101 Signaling Pathway in Pancreatic Ductal Adenocarcinoma"],"prefix":"10.1096","volume":"40","author":[{"given":"Jianhua","family":"Bai","sequence":"first","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery. The First People's Hospital of Yunnan Province The Affiliated Hospital of Kunming University of Science and Technology  Kunming Yunnan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihe","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery. The First People's Hospital of Yunnan Province The Affiliated Hospital of Kunming University of Science and Technology  Kunming Yunnan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4685-6408","authenticated-orcid":false,"given":"Chern","family":"Ein Oon","sequence":"additional","affiliation":[{"name":"Institute for Research in Molecular Medicine Universiti Sains Malaysia  Minden Pulau Pinang Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingping","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery. 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The First People's Hospital of Yunnan Province The Affiliated Hospital of Kunming University of Science and Technology  Kunming Yunnan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liman","family":"Yang","sequence":"additional","affiliation":[{"name":"First Clinical Medical College Yunnan University of Chinese Medicine  Kunming Yunnan China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amirabas","family":"Bostani","sequence":"additional","affiliation":[{"name":"Department of Biology, Science &amp; Research Institute Islamic Azad University  Tehran Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhao","family":"Fei","sequence":"additional","affiliation":[{"name":"Department of Hepatopancreatobiliary Surgery. 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