Acinar-ductal metaplasia in pancreatitis and pancreatic ductal adenocarcinoma

Acinar-ductal metaplasia (ADM) represents a dynamic and reversible cellular adaptation in the pancreas, whereby acinar cells dedifferentiate and transdifferentiate into duct-like cells in response to inflammatory, metabolic, and environmental stressors. While transient ADM facilitates tissue repair after acute injury, persistent stimuli-including chronic pancreatitis, metabolic dysregulation, obesity, diabetes, smoking, and oncogenic KRAS mutations-stabilize ADM and promote progression to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). ADM is orchestrated by integrated signaling networks involving TGF-β/SMAD, EGFR-KRAS-MAPK, PI3K-AKT-mTOR, Notch, Wnt/β-catenin, and JAK/STAT3, which regulate dedifferentiation, proliferation, survival, and fibrosis. Inflammatory cells, particularly macrophages and eosinophils, and pro-inflammatory cytokines such as IL‑6, IL‑18, and TNF‑α 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.