Non-alcoholic fatty pancreas disease (NAFPD) as a pre-neoplastic niche: Metabolic and inflammatory Gateways to pancreatic ductal adenocarcinoma

Non-alcoholic fatty pancreas disease (NAFPD), marked by ectopic triglyceride accumulation in the exocrine pancreas, is increasingly observed yet its recognition as a cancer-predisposing condition remains limited. We synthesize evidence supporting NAFPD as an early and modifiable niche for pancreatic ductal adenocarcinoma (PDAC), using a PRISMA-ScR-guided framework. The findings were synthesized into three domains: epidemiological risk, metabolic-inflammatory signaling, and immune-stromal remodeling. Mechanisms include palmitate-induced ER stress, ROS-driven NLRP3-IL-1β and STAT5 signaling, and KRAS^G12D-mediated lipotoxicity. Lipid-laden stellate cells promote fibrosis, immunosuppression, and epithelial-mesenchymal transition. NAFPD may represent an early, modifiable PDAC niche, warranting further imaging-omic studies and targeted prevention trials.