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While transient ADM facilitates tissue repair after acute injury, persistent stimuli\u2014including chronic pancreatitis, metabolic dysregulation, obesity, diabetes, smoking, and oncogenic KRAS mutations\u2014stabilize ADM and promote progression to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). ADM is orchestrated by integrated signaling networks involving TGF-\u03b2\/SMAD, EGFR\u2013KRAS\u2013MAPK, PI3K\u2013AKT\u2013mTOR, Notch, Wnt\/\u03b2-catenin, and JAK\/STAT3, which regulate dedifferentiation, proliferation, survival, and fibrosis. Inflammatory cells, particularly macrophages and eosinophils, and pro-inflammatory cytokines such as IL\u20116, IL\u201118, and TNF\u2011\u03b1 further amplify ADM and create a tumor-promoting microenvironment. Single-cell analyses reveal that ADM encompasses heterogeneous cell states with distinct lineage trajectories, determining reversibility or pre-neoplastic transformation. Pharmacological interventions, including HDAC inhibitors, JAK\/STAT3 inhibitors, metformin, and anti-inflammatory agents, show potential in preventing or reversing ADM. Understanding the complex molecular, cellular, and environmental regulation of ADM provides critical insights into pancreatic regeneration and early tumorigenesis and offers a framework for developing targeted strategies for the prevention and treatment of pancreatitis and PDAC.<\/jats:p>","DOI":"10.1007\/s13402-026-01251-0","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T19:44:33Z","timestamp":1782762273000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Acinar-ductal metaplasia in pancreatitis and pancreatic ductal adenocarcinoma"],"prefix":"10.1007","volume":"49","author":[{"given":"Xiangyu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeru","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiping","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutong","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lirui","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haoyu","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weibin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"issue":"2","key":"1251_CR1","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1111\/j.1469-185X.1978.tb01437.x","volume":"53","author":"RM Case","year":"1978","unstructured":"R.M. 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