ArticleNature communications2025
Biochemical analyses of cystatin-C dimers and cathepsin-B reveals a trypsin-driven feedback mechanism in acute pancreatitis.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed.
- Interleukin-1α Mediates Pancreatic Fibroblast Activation, Regulates Immune Cell Recruitment and Fibrosis in Acute and Chronic Pancreatitis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Identification of factors conferring resistance to trastuzumab deruxtecan in advanced gastric cancer: a translational study from the single-arm, phase II, DESTINY-Gastric06 trial.Precision clinical medicine · 2026Article
- IL-4/STAT6-signaling Influences Local Inflammation and Regeneration Processes During Acute Pancreatitis and Promotes Fibrosis by a Direct Activation of Pancreatic Fibroblasts During Chronic Pancreatitis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Article
- Pathologically relevant trypsinogen activation in pancreatitis.American journal of physiology. Gastrointestinal and liver physiology · 2026Review
- Demystifying anti-inflammatory therapeutic strategies against pancreatitis and concomitant diseases: a 2025 perspective.Theranostics · 2026Review
- Role of Interleukin-6 Mediated T Cell Activation in Experimental Acute Pancreatitis.Inflammation · 2025Article
- Spatial- and Phospho-Proteomic Profiling Reveals Pancreatic and Hepatic Dysfunction in a Rat Model of Lethal Insulin Overdose.International journal of molecular sciences · 2025Article
- Translational Pharmaco-Nutritional Approaches in the Management of Clinical Acute Pancreatitis-A Narrative Review.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Host proteases: key regulators in viral infection and therapeutic targeting.Frontiers in immunology · 2025Review
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Authors and funding
22 authors.
Funding
Abstract
Acute pancreatitis (AP) is characterised by self-digestion of the pancreas by its own proteases. This pathophysiological initiating event in AP occurs inside pancreatic acinar cells where intrapancreatic trypsinogen becomes prematurely activated by cathepsin B (CTSB), and induces the digestive protease cascade, while cathepsin L (CTSL) degrades trypsin and trypsinogen and therefore prevents the development of AP. These proteases are located in the secretory compartment of acinar cells together with cystatin C (CST3), an endogenous inhibitor of CTSB and CTSL. The results are based on detailed biochemical analysis, site-directed mutagenesis and molecular dynamics simulations in combination with an experimental disease model of AP using CST3 deficient mice. This identifies that CST3 is a critical regulator of CTSB and CTSL activity during AP. CST3 deficient mice show a higher intracellular CTSB activity resulting in elevated trypsinogen activation accompanied by an increased disease severity. This reveals that CST3 can be cleaved by trypsin disabling the inhibition of CTSB, but not of CTSL. Furthermore, dimerised CST3 enhances the CTSB activity by binding to an allosteric pocket specific to the CTSB structure. CST3 shifts from an inhibitor to an activator of CTSB and therefore fuels the intrapancreatic protease cascade during the onset of AP.
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