PNLIPRP1 (pancreatic lipase-related protein 1) is a pancreatic exocrine enzyme that may function as an inhibitor of dietary triglyceride digestion, lacking detectable lipase activity toward triglycerides and related lipid substrates 1. The protein participates in lipid metabolism and cholesterol homeostasis pathways. Mechanistically, PNLIPRP1 expression is regulated by DNA methylation in the exocrine pancreas; T2D causally induces PNLIPRP1 hypermethylation, which in turn causally affects LDL cholesterol levels 1. PNLIPRP1 knockdown in pancreatic acinar cells triggers acinar-to-ductal metaplasia, a precancerous state 1. Disease relevance: PNLIPRP1 null variants are associated with elevated glycemia and LDL cholesterol 1, and genetic variants colocalizing with Type 1 diabetes GWAS signals causally implicate PNLIPRP1 in T1D pathogenesis 2. PNLIPRP1 expression is significantly downregulated in pancreatic ductal adenocarcinoma 34, and reduced lipolytic pathway function involving PNLIPRP1 associates with impaired free fatty acid metabolism and altered pancreatic cancer progression 5. Clinical significance: PNLIPRP1 represents a potential therapeutic target for metabolic diseases and pancreatic malignancy, with epigenetic and genetic mechanisms linking it to cardiometabolic disease risk.