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J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, and approximately 15% of cases arise from intraductal papillary mucinous neoplasms (IPMNs). These precursor lesions can progress to invasive cancer through the accumulation of molecular alterations. To identify pathways associated with this transition, we performed comparative transcriptomic analyses of patient-derived IPMN and PDAC samples, followed by protein-level validation in tissue specimens and pancreatic cancer cell lines. Functional studies were conducted using the selective p38\u03b1 inhibitor ralimetinib in two-dimensional cultures, three-dimensional tumorspheres, and patient-derived tumor organoids (PDTOs). Transcriptomic profiling revealed significant downregulation of the p38 pathway in IPMNs compared with PDAC, suggesting progressive pathway activation during pancreatic tumorigenesis. Immunohistochemical analyses confirmed increased phospho-activated p38\u03b1 in PDAC tissues, particularly in lesions with advanced malignant features, while PDAC cell lines displayed higher levels of activated p38\u03b1 than non-tumorigenic pancreatic epithelial cells. Pharmacological inhibition of p38\u03b1 suppressed downstream MAPKAPK2 phosphorylation, induced apoptotic cell death, and reduced tumorsphere growth and viability. Consistently, PDTOs exhibiting elevated p38\u03b1 activation showed increased sensitivity to ralimetinib treatment. Collectively, these findings identify p38\u03b1 signaling as a pathway activated during PDAC progression and support further investigation of p38\u03b1-targeted therapies as a potential precision medicine strategy for pancreatic cancer.<\/jats:p>","DOI":"10.3390\/ijms27198550","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T16:29:53Z","timestamp":1790267393000},"page":"8550","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["p38\u03b1 Signaling Is Associated with Pancreatic Ductal Adenocarcinoma Progression and Represents a Potential Therapeutic Vulnerability"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-7940-4977","authenticated-orcid":false,"given":"Ilaria","family":"Grassi","sequence":"first","affiliation":[{"name":"Histopathology Unit, National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d Research Hospital, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5880-9514","authenticated-orcid":false,"given":"Elisabetta","family":"Di Nicola","sequence":"additional","affiliation":[{"name":"Medical Genetics, National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d Research Hospital, Castellana Grotte, 70013 Bari, Italy"},{"name":"Department of Molecular Medicine, University of Rome La Sapienza, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erica","family":"Candela","sequence":"additional","affiliation":[{"name":"Medical Genetics, National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d Research Hospital, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2952-0053","authenticated-orcid":false,"given":"Elisabetta","family":"Cavalcanti","sequence":"additional","affiliation":[{"name":"Histopathology Unit, National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d Research Hospital, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6798-808X","authenticated-orcid":false,"given":"Annamaria","family":"Valentini","sequence":"additional","affiliation":[{"name":"Histopathology Unit, National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d Research Hospital, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonardo","family":"Vincenti","sequence":"additional","affiliation":[{"name":"Department of General Surgery, National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d Research Hospital, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7442-1996","authenticated-orcid":false,"given":"Carla","family":"Santoiemma","sequence":"additional","affiliation":[{"name":"Medical Genetics, National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d Research Hospital, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3843-1618","authenticated-orcid":false,"given":"Valentina","family":"Grossi","sequence":"additional","affiliation":[{"name":"Medical Genetics, National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d Research Hospital, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3794-7834","authenticated-orcid":false,"given":"Martina","family":"Lepore Signorile","sequence":"additional","affiliation":[{"name":"Medical Genetics, National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d Research Hospital, Castellana Grotte, 70013 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiano","family":"Simone","sequence":"additional","affiliation":[{"name":"Medical Genetics, National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d Research Hospital, Castellana Grotte, 70013 Bari, Italy"},{"name":"Department of Precision and Regenerative Medicine and Jonic Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1661-5504","authenticated-orcid":false,"given":"Raffaele","family":"Armentano","sequence":"additional","affiliation":[{"name":"Histopathology Unit, National Institute of Gastroenterology, IRCCS \u201cSaverio de Bellis\u201d Research Hospital, Castellana Grotte, 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