The CPA1S282P Mutation Leading to Chronic Pancreatitis in Rabbits

Chronic pancreatitis (CP) is a progressive, irreversible inflammatory and fibrotic condition that increases the risk for pancreatic cancer, with no specific treatments currently available. The carboxypeptidase A1 p.Ser282Pro (CPA1S282P) variant has been associated with CP, potentially involving misfolding-induced endoplasmic reticulum stress (ERS), although additional mechanisms remain underexplored. We generated a rabbit model to mimic the human CPA1S282P mutation using the SpRY-ABE-8.17 system. CPA1S282P homozygous rabbits exhibited characteristic human CP phenotypes following alcohol induction, including visceral pain, elevated serum pancreatic lipase and amylase, inflammatory cell infiltration, and fibrosis. Importantly, mutation p.S282P induced misfolding of CPA1 and resulted in elevated expression of ERS markers GRP78 and CHOP both in HEK 293T cells and homozygous mutant rabbits. Further investigation revealed that the CPA1S282P mutation disturbed intra-pancreatic lipid metabolism, leading to the development of CP in CPA1S282P rabbits. This study presents the first rabbit model of CP disease that accurately replicates a specific point mutation observed in humans. Additionally, the study provides further insights into the connection between CPA1 and intra-pancreatic lipid metabolism, offering valuable information for developing novel therapeutic targets for human CP.