CPA1^S282P mutation leads to chronic pancreatitis in rabbits

Chronic pancreatitis (CP) is a progressive and irreversible fibroinflammatory disease that markedly increases susceptibility to pancreatic cancer and remains without effective targeted therapies. Among the genetic contributors to CP, the carboxypeptidase A1 p.Ser282Pro (CPA1^S282P) variant has been proposed to promote disease through misfolding-induced endoplasmic reticulum stress (ERS), although the broader pathogenic landscape remains incompletely defined. This study generated a rabbit model mimicking the human CPA1^S282P mutation using the SpRY-ABE-8.17 system. Homozygous CPA1^S282P rabbits exhibited characteristic human CP phenotypes following alcohol induction, including visceral pain, elevated serum lipase and amylase, inflammatory cell infiltration, and extensive pancreatic fibrosis. Biochemical analyses confirmed that the p.S282P mutation induced CPA1 misfolding and elevated the expression of ERS markers GRP78 and CHOP in both transfected HEK293T cells and homozygous mutant rabbits. Notably, the CPA1^S282P mutation markedly disrupted intra-pancreatic lipid homeostasis, contributing to the development of CP in mutant rabbits. This study successfully established the first rabbit model of CP that accurately recapitulates CP caused by a defined human point mutation. Additionally, this study provides insights into a previously unrecognized link between CPA1 and intra-pancreatic lipid metabolism, offering a foundation for identifying novel therapeutic targets for human CP.