Authors
Du, Z., Weber, L., Buettner, U. F. G., Gerstenlauer, M., Manfras, U., Steiger, K., Metzler, T., Chan, L. K., Mulaw, M., Tsesmelis, M., Wirth, T.
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.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 16 Oct 2026.
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