Heparanase 2 (Hpa2) protects the exocrine pancreas from damages of Western diet and pancreatic cancer.

Fatty pancreas and pancreatitis are increasingly linked to Western dietary patterns and pancreatic cancer risk, yet intrinsic molecular mechanisms that preserve pancreatic identity under metabolic stress remain insufficiently defined. Heparanase-2 (Hpa2), a homolog of heparanase that lacks heparan sulfate-degrading activity, is clinically associated with favorable cancer outcomes, but its role in pancreatic homeostasis remains poorly defined. We fed wild-type (WT) and conditional Hpa2 knockout (Hpa2-KO) mice with a high-fat diet (HFD) and integrated histopathologic, transcriptomic, and proteomic analyses to define diet-dependent pancreatic responses. HFD elicited profound pancreatic remodeling selectively in Hpa2-KO mice, marked by massive fatty infiltration (fatty pancreas), extensive acinar-to-ductal metaplasia, β-islet hyperplasia, fibrosis, and pancreatic intraepithelial neoplasia (PanIN). These changes coincided with a decrease in acinar lineage identity, as reflected by marked suppression of GATA4, GATA6, MIST1, and PDX1. Systems-level analyses identified mTORC1 as a dominant signaling hub linking Hpa2 deficiency to metabolic reprogramming, with unanticipated effects on mitochondrial oxidative phosphorylation and ribosomal function. The results strongly imply that Hpa2 functions critically in preserving exocrine pancreatic identity and suppressing Western diet-driven pancreatic injury and neoplastic progression. Loss of Hpa2 advances diet-induced pancreatic disease, positioning Hpa2 as a key regulator of fatty pancreas, pancreatitis, and pancreatic cancer risk.