{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T18:17:09Z","timestamp":1793297829482,"version":"4.5.0"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T00:00:00Z","timestamp":1761091200000},"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>Background<\/jats:title>\n                    <jats:p>Ferroptosis, a regulated form of iron-dependent cell death, has shown promise as an anti-tumor mechanism. However, its role in pancreatic cancer remains largely unexplored. This study aimed to identify a ferroptosis-related prognostic signature and key biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Transcriptomic profiles and clinical data of pancreatic cancer patients were obtained from the GEO and TCGA databases. A prognostic signature was constructed using LASSO and Cox regression analysis. The role of a key gene, NOTCH2, was investigated through somatic mutation, functional enrichment, immune infiltration, and drug sensitivity analysis.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , the expression of NOTCH2 was confirmed by Western blot, and its effects on cell proliferation and migration were assessed using MTT, colony formation, and wound-healing assays. Its involvement in ferroptosis was further investigated by measuring intracellular iron, reactive oxygen species (ROS) and C11-BODIPY.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We constructed and validated a ferroptosis-related prognostic signature consisting of NOTCH2, KRT18, and H1-2. Patients in the high-risk group, as defined by this signature, exhibited significantly worse overall survival. A nomogram integrating the risk score and clinical variables demonstrated excellent accuracy in predicting patient prognosis. We identified NOTCH2 as a key biomarker, showing upregulated expression in pancreatic cancer tissues and cell lines, which correlated with poor prognosis and increased infiltration of M2 macrophages. Functionally, knockdown of NOTCH2\n                      <jats:italic>in vitro<\/jats:italic>\n                      inhibited the proliferation and migration of pancreatic cancer cells while increasing both intracellular iron concentration and lipid peroxidation levels.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study establishes a ferroptosis-related signature for prognostic prediction in pancreatic cancer and identifies NOTCH2 as a critical prognostic biomarker. NOTCH2 may promote pancreatic cancer progression by suppressing ferroptosis, highlighting it as a potential therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1659652","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T05:33:08Z","timestamp":1761111188000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Development of a ferroptosis-related signature and identification of NOTCH2 as a novel prognostic biomarker in pancreatic cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Siyi","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Oncology, The Affiliated Hospital of Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxuan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Affiliated Hospital of Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang-Xue","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Affiliated Hospital of Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zi-Heng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Affiliated Hospital of Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Hui","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Huangdao District People\u2019s Hospital","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Oncology, The Affiliated Hospital of Qingdao 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