{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T03:55:06Z","timestamp":1781495706705,"version":"3.54.1"},"reference-count":362,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T00:00:00Z","timestamp":1781308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Pancreatic ductal adenocarcinoma (PDAC) belongs to the group of killer human cancers. Its ferocity is sustained by an unusual mix of genetic changes\u2014primarily in KRAS and TP53\u2014a hypoxic as well as desmoplastic tumor microenvironment, plus metabolic and redox adaptations that allow tumor life amidst intense stress situations. Content: This paper will discuss the molecular networks of wild-type and mutant p53, wild-type and mutant KRAS, PUMA, TIGAR, PRMT5, NRF2, oxygen tension, reactive oxygen species (ROS), and oxidative stress pathways that contribute to pancreatic cancer. It will describe how these factors help set the tumor\u2019s redox state and control apoptosis and therapeutic resistance. This shall therefore specifically discuss what role oxygen gradients play in pancreatic tissues, as well as retinoic acid, together with redox-targeted therapies that are specific to vulnerabilities within such types of networks. Summary and Outlook: An understanding of the crosstalk of these molecular pathways will be critical in designing rational therapeutic strategies. Genetics, metabolism, and microenvironmental integration may open a path toward combinatorial therapies that would resensitize PDAC to apoptosis and overcome resistance to current treatments.<\/jats:p>","DOI":"10.3390\/cancers18121932","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T03:01:27Z","timestamp":1781492487000},"page":"1932","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Focus on the Interactive Cooperation Among Mechanotransduction and Biochemical Processes in Pancreatic Ductal Adenocarcinoma Development and Possible Adjuvant Role of Retinoic Acid for Its Treatment: A Narrative Review"],"prefix":"10.3390","volume":"18","author":[{"given":"Sirio","family":"Fiorino","sequence":"first","affiliation":[{"name":"Internal Medicine Unit, Budrio Hospital, Budrio (Bologna), Azienda USL, 40065 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6857-4252","authenticated-orcid":false,"given":"Wandong","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0609-8817","authenticated-orcid":false,"given":"Dario","family":"de Biase","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology (FaBit), University of Bologna, 40126 Bologna, Italy"},{"name":"Solid Tumor Molecular Pathology Laboratory, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Mastrangelo","sequence":"additional","affiliation":[{"name":"Department of Surgery, AOU Sant\u2019Orsola Malpighi, IRCCS Azienda Ospedaliera Universitaria, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7599-0289","authenticated-orcid":false,"given":"Francesca","family":"Maccioni","sequence":"additional","affiliation":[{"name":"Department of Radiological, Oncological and Pathological Sciences, Umberto I Hospital, Sapienza University of Rome, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4793-9766","authenticated-orcid":false,"given":"Alfonso","family":"Grottesi","sequence":"additional","affiliation":[{"name":"Unit of General Surgery, Sandro Pertini Hospital, 00157 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ambrosi","sequence":"additional","affiliation":[{"name":"Pathology Unit, DIAP\u2014Dipartimento Interaziendale Anatomia Patologica, Maggiore Hospital-AUSL Bologna, 40133 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-9806-2789","authenticated-orcid":false,"given":"Luca","family":"Pincigher","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology (FaBit), University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Lari","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit, Budrio Hospital, Budrio (Bologna), Azienda USL, 40065 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4387-5117","authenticated-orcid":false,"given":"Christian","family":"Bergamini","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Biotechnology (FaBit), University of Bologna, 40126 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elio","family":"Jovine","sequence":"additional","affiliation":[{"name":"Department of Surgery, AOU Sant\u2019Orsola Malpighi, IRCCS Azienda Ospedaliera Universitaria, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5876-3199","authenticated-orcid":false,"given":"Maddalena","family":"Zippi","sequence":"additional","affiliation":[{"name":"Unit of Gastroenterology and Digestive Endoscopy, Sandro Pertini Hospital, 00157 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"173","DOI":"10.4251\/wjgo.v12.i2.173","article-title":"Pancreatic ductal adenocarcinoma: Treatment hurdles, tumor microenvironment and immunotherapy","volume":"12","author":"Sarantis","year":"2020","journal-title":"World J. 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