Chemogenomic Screening in a Patient‐Derived 3D Fatty Liver Disease Model Reveals the CHRM1‐TRPM8 Axis as a Novel Module for Targeted Intervention
Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of chronic liver disease with few therapeutic options. To narrow the translational gap in the development of pharmacological MASH treatments, a 3D liver model from primary human hepatocytes and non-parenchymal cells derived from patients with histologically confirmed MASH was established. The model closely mirrors disease-relevant endpoints, such as steatosis, inflammation and fibrosis, and multi-omics analyses show excellent alignment with biopsy data from 306 MASH patients and 77 controls. By combining high-content imaging with scalable biochemical assays and chemogenomic screening, multiple novel targets with anti-steatotic, anti-inflammatory, and anti-fibrotic effects are identified. Among these, activation of the muscarinic M<sub>1</sub> receptor (CHRM1) and inhibition of the TRPM8 cation channel result in strong anti-fibrotic effects, which are confirmed using orthogonal genetic assays. Strikingly, using biosensors based on bioluminescence resonance energy transfer, a functional interaction along a novel MASH signaling axis in which CHRM1 inhibits TRPM8 via G<sub>q/11</sub> and phospholipase C-mediated depletion of phosphatidylinositol 4,5-bisphosphate can be demonstrated. Combined, this study presents the first patient-derived 3D MASH model, identifies a novel signaling module with anti-fibrotic effects, and highlights the potential of organotypic culture systems for phenotype-based chemogenomic drug target identification at scale.
Authors
- Andreas J. Hülsmeier
- M. Sundström (ORCID: https://orcid.org/0009-0000-4972-5481)
- Roberto Gramignoli (ORCID: https://orcid.org/0000-0003-3362-4170)
- Nuria Oliva‐Vilarnau (ORCID: https://orcid.org/0000-0002-3083-6701)
- Ming-Mei Shang (ORCID: https://orcid.org/0000-0002-4480-6095)
- Niklas K. Björkström (ORCID: https://orcid.org/0000-0002-0967-076X)
- Jonas Schreiner (ORCID: https://orcid.org/0000-0002-7371-5109)
- Shane C. Wright (ORCID: https://orcid.org/0000-0002-7470-5068)
- Martin Cornillet (ORCID: https://orcid.org/0000-0001-7981-0927)
- Thorsten Hornemann (ORCID: https://orcid.org/0000-0002-4218-1087)
- Pierre Sabatier (ORCID: https://orcid.org/0000-0002-2734-1791)
- Florian Büttner (ORCID: https://orcid.org/0000-0002-0657-9522)
- Maike Windbergs (ORCID: https://orcid.org/0000-0001-9475-699X)
- Aimo Kannt (ORCID: https://orcid.org/0000-0002-5197-2286)
- Brinton A. Seashore-Ludlow (ORCID: https://orcid.org/0000-0001-8658-5967)
- Volker Martin Lauschke (ORCID: https://orcid.org/0000-0002-1140-6204)
- Sonia Youhanna (ORCID: https://orcid.org/0000-0002-9376-8478)
- Aurino M. Kemas (ORCID: https://orcid.org/0000-0001-9031-4748)
- Maurice Michel (ORCID: https://orcid.org/0000-0003-3261-2493)
- Britta Klumpp
- Yi Zhong (ORCID: https://orcid.org/0000-0002-0929-8224)
- Aikaterini Motso (ORCID: https://orcid.org/0009-0003-8992-0312)
- Hongda Sheng
- Kathrin Klein (ORCID: https://orcid.org/0000-0001-9819-2773)
- Yi Wang (ORCID: https://orcid.org/0000-0001-9048-0092)
- Jesper Olsen (ORCID: https://orcid.org/0000-0002-2318-9593)
- Nicole Ziegler (ORCID: https://orcid.org/0009-0002-4626-8793)
Institutions
- Goethe University Frankfurt (DE)
- Uppsala University (SE)
- University of Copenhagen (DK)
- Tianjin University of Traditional Chinese Medicine (CN)
- Karolinska University Hospital (SE)
- Central South University (CN)
- University of Zurich (CH)
- Science for Life Laboratory (SE)
- Novo Nordisk Foundation (DK)
- Karolinska Institutet (SE)
- University Hospital of Zurich (CH)
- Fraunhofer Institute for Translational Medicine and Pharmacology (DE)
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology (DE)
- Second Xiangya Hospital of Central South University (CN)
- Zhejiang University (CN)
- University of Tübingen (DE)
Publication Details
- Journal
- Advanced Science
- Published
- 2024-11-28
- DOI
- https://doi.org/10.1002/advs.202407572
- Citations
- 18
- Primary Topic
- Liver Disease Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 6.96
Funders
- Åke Wiberg Stiftelse
- McGill University
- Diamond Light Source
- European Federation of Pharmaceutical Industries and Associations
- European Commission
- Robert Bosch Stiftung
- Svenska Sällskapet för Medicinsk Forskning
- Knut och Alice Wallenbergs Stiftelse
- Novo Nordisk
- Vetenskapsrådet
- Université de Bordeaux
- Science for Life Laboratory
- Novo Nordisk Fonden
- H2020 Society
- FP7 Ideas: European Research Council