NIK stabilization reprograms the pancreas toward chronic pancreatitis and pancreatic lipomatosis
- 1Single-Cell Sequencing Unit, University of Ulm
Abstract
Pancreatic lipomatosis, characterized by progressive adipose replacement of the exocrine pancreas, is a known consequence of chronic pancreatitis. Despite its clinical relevance, the mechanisms driving lipomatosis remain poorly understood. Here, we used a pancreas-specific NF-{kappa}B-inducing kinase (NIK) stabilization mouse model to investigate how sustained non-canonical NF-{kappa}B signaling contributes to chronic pancreatitis and pancreatic lipomatosis. NIK stabilization initiated a rapid and fully penetrant pancreatic remodeling program, leading to acinar cell death already by the end of the first week of age. Deep learning on high-definition spatial transcriptomics revealed a progressive loss of acinar identity resulting in acinar-to-ductal metaplasia (ADM) formation and identified GPA33 as a novel surface marker of ADMs. Over time, ADM lesions underwent apoptosis, leading to progressive loss of pancreatic parenchyma, organ atrophy, and extensive adipose replacement. Mechanistically, Relb deletion fully rescued the NIK-induced pancreatic phenotype, demonstrating that chronic pancreatitis and lipomatosis require RelB-dependent non-canonical NF-{kappa}B signaling in this model. Together, these findings define a RelB-dependent pathway linking sustained NIK stabilization to chronic pancreatitis and pancreatic lipomatosis. Our study provides a model for studying the development of pancreatic lipomatosis and for exploring potential therapeutic approaches.
Related
- Canadian National Pancreas Conference 2025: Recent Advances in Patient-Centred Management of Pancreatic Cancer.
- Spiral Jejunal Reconstruction of Both Pancreatic Stumps in Type II Portal Annular Pancreas during Pancreaticoduodenectomy: A Case Report
- Intrahepatic and Intrasplenic Pancreatic Pseudocysts Following Acute Pancreatitis: A Case Report
- Endoscopic management of pancreatic duct stones and stricture in chronic pancreatitis using a fully covered self-expandable metal stent.
- Spontaneous fistulization of a giant pancreatic pseudocyst into the duodenum following acute pancreatitis: a case report
BibTeX
@misc{du2026stabilization,
title = {{NIK stabilization reprograms the pancreas toward chronic pancreatitis and pancreatic lipomatosis}},
author = {Z. Du and L. Weber and U. F. G. Buettner and M. Gerstenlauer and U. Manfras and K. Steiger and T. Metzler and L. K. Chan and M. Mulaw and M. Tsesmelis and T. Wirth},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.07.757290},
url = {https://www.biorxiv.org/content/10.64898/2026.10.07.757290v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - NIK stabilization reprograms the pancreas toward chronic pancreatitis and pancreatic lipomatosis
AU - Z. Du
AU - L. Weber
AU - U. F. G. Buettner
AU - M. Gerstenlauer
AU - U. Manfras
AU - K. Steiger
AU - T. Metzler
AU - L. K. Chan
AU - M. Mulaw
AU - M. Tsesmelis
AU - T. Wirth
PY - 2026
DA - 2026/10/07
PB - bioRxiv
DO - 10.64898/2026.10.07.757290
UR - https://www.biorxiv.org/content/10.64898/2026.10.07.757290v1
AB - Pancreatic lipomatosis, characterized by progressive adipose replacement of the exocrine pancreas, is a known consequence of chronic pancreatitis. Despite its clinical relevance, the mechanisms driving lipomatosis remain poorly understood. Here, we used a pancreas-specific NF-{kappa}B-inducing kinase (NIK) stabilization mouse model to investigate how sustained non-canonical NF-{kappa}B signaling contributes to chronic pancreatitis and pancreatic lipomatosis. NIK stabilization initiated a rapid and fully penetrant pancreatic remodeling program, leading to acinar cell death already by the end of the first week of age. Deep learning on high-definition spatial transcriptomics revealed a progressive loss of acinar identity resulting in acinar-to-ductal metaplasia (ADM) formation and identified GPA33 as a novel surface marker of ADMs. Over time, ADM lesions underwent apoptosis, leading to progressive loss of pancreatic parenchyma, organ atrophy, and extensive adipose replacement. Mechanistically, Relb deletion fully rescued the NIK-induced pancreatic phenotype, demonstrating that chronic pancreatitis and lipomatosis require RelB-dependent non-canonical NF-{kappa}B signaling in this model. Together, these findings define a RelB-dependent pathway linking sustained NIK stabilization to chronic pancreatitis and pancreatic lipomatosis. Our study provides a model for studying the development of pancreatic lipomatosis and for exploring potential therapeutic approaches.
ER -