Chemogenomic Screening in a Patient‐Derived 3D Fatty Liver Disease Model Reveals the CHRM1‐TRPM8 Axis as a Novel Module for Targeted Intervention
Abstract 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...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-01-01
|
| Series: | Advanced Science |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/advs.202407572 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832593566456610816 |
|---|---|
| author | Sonia Youhanna Aurino M. Kemas Shane C. Wright Yi Zhong Britta Klumpp Kathrin Klein Aikaterini Motso Maurice Michel Nicole Ziegler Mingmei Shang Pierre Sabatier Aimo Kannt Hongda Sheng Nuria Oliva‐Vilarnau Florian A. Büttner Brinton Seashore‐Ludlow Jonas Schreiner Maike Windbergs Martin Cornillet Niklas K. Björkström Andreas J. Hülsmeier Thorsten Hornemann Jesper V. Olsen Yi Wang Roberto Gramignoli Michael Sundström Volker M. Lauschke |
| author_facet | Sonia Youhanna Aurino M. Kemas Shane C. Wright Yi Zhong Britta Klumpp Kathrin Klein Aikaterini Motso Maurice Michel Nicole Ziegler Mingmei Shang Pierre Sabatier Aimo Kannt Hongda Sheng Nuria Oliva‐Vilarnau Florian A. Büttner Brinton Seashore‐Ludlow Jonas Schreiner Maike Windbergs Martin Cornillet Niklas K. Björkström Andreas J. Hülsmeier Thorsten Hornemann Jesper V. Olsen Yi Wang Roberto Gramignoli Michael Sundström Volker M. Lauschke |
| author_sort | Sonia Youhanna |
| collection | DOAJ |
| description | Abstract 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 M1 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 Gq/11 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. |
| format | Article |
| id | doaj-art-b218a152bada4f5f821eb7759449ee03 |
| institution | Kabale University |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-b218a152bada4f5f821eb7759449ee032025-01-20T13:04:18ZengWileyAdvanced Science2198-38442025-01-01123n/an/a10.1002/advs.202407572Chemogenomic Screening in a Patient‐Derived 3D Fatty Liver Disease Model Reveals the CHRM1‐TRPM8 Axis as a Novel Module for Targeted InterventionSonia Youhanna0Aurino M. Kemas1Shane C. Wright2Yi Zhong3Britta Klumpp4Kathrin Klein5Aikaterini Motso6Maurice Michel7Nicole Ziegler8Mingmei Shang9Pierre Sabatier10Aimo Kannt11Hongda Sheng12Nuria Oliva‐Vilarnau13Florian A. Büttner14Brinton Seashore‐Ludlow15Jonas Schreiner16Maike Windbergs17Martin Cornillet18Niklas K. Björkström19Andreas J. Hülsmeier20Thorsten Hornemann21Jesper V. Olsen22Yi Wang23Roberto Gramignoli24Michael Sundström25Volker M. Lauschke26HepaPredict AB Stockholm 17165 SwedenDepartment of Physiology and Pharmacology Karolinska Institutet Stockholm 17165 SwedenDepartment of Physiology and Pharmacology Karolinska Institutet Stockholm 17165 SwedenDepartment of Physiology and Pharmacology Karolinska Institutet Stockholm 17165 SwedenDr. Margarete Fischer‐Bosch Institute of Clinical Pharmacology (IKP) 70376 Stuttgart GermanyDr. Margarete Fischer‐Bosch Institute of Clinical Pharmacology (IKP) 70376 Stuttgart GermanyDepartment of Physiology and Pharmacology Karolinska Institutet Stockholm 17165 SwedenCenter for Molecular Medicine Karolinska Institutet and University Hospital Stockholm 17176 SwedenFraunhofer Institute for Translational Medicine and Pharmacology (ITMP) 60596 Frankfurt am Main GermanyCenter for Molecular Medicine Karolinska Institutet and University Hospital Stockholm 17176 SwedenNovo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences University of Copenhagen Copenhagen 2200 DenmarkFraunhofer Institute for Translational Medicine and Pharmacology (ITMP) 60596 Frankfurt am Main GermanyDepartment of Physiology and Pharmacology Karolinska Institutet Stockholm 17165 SwedenDepartment of Physiology and Pharmacology Karolinska Institutet Stockholm 17165 SwedenDr. Margarete Fischer‐Bosch Institute of Clinical Pharmacology (IKP) 70376 Stuttgart GermanyDepartment of Oncology and Pathology Science for Life Laboratory Karolinska Institutet Stockholm 17164 SwedenInstitute of Pharmaceutical Technology Goethe University Frankfurt 60438 Frankfurt am Main GermanyInstitute of Pharmaceutical Technology Goethe University Frankfurt 60438 Frankfurt am Main GermanyCentre for Infectious Medicine Department of Medicine Huddinge Karolinska University Hospital Karolinska Institutet Huddinge 14152 SwedenCentre for Infectious Medicine Department of Medicine Huddinge Karolinska University Hospital Karolinska Institutet Huddinge 14152 SwedenUniversity of Zurich University Hospital Zurich Institute of Clinical Chemistry Zurich 8091 SwitzerlandUniversity of Zurich University Hospital Zurich Institute of Clinical Chemistry Zurich 8091 SwitzerlandNovo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences University of Copenhagen Copenhagen 2200 DenmarkPharmaceutical Informatics Institute College of Pharmaceutical Sciences Zhejiang University Hangzhou Zhejiang 310058 ChinaDepartment of Laboratory Medicine Division of Pathology Karolinska Institutet Stockholm 17177 SwedenCenter for Molecular Medicine Karolinska Institutet and University Hospital Stockholm 17176 SwedenHepaPredict AB Stockholm 17165 SwedenAbstract 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 M1 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 Gq/11 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.https://doi.org/10.1002/advs.202407572chemical probesfibrosismuscarinic receptorNASHphenotypic assaytarget discovery |
| spellingShingle | Sonia Youhanna Aurino M. Kemas Shane C. Wright Yi Zhong Britta Klumpp Kathrin Klein Aikaterini Motso Maurice Michel Nicole Ziegler Mingmei Shang Pierre Sabatier Aimo Kannt Hongda Sheng Nuria Oliva‐Vilarnau Florian A. Büttner Brinton Seashore‐Ludlow Jonas Schreiner Maike Windbergs Martin Cornillet Niklas K. Björkström Andreas J. Hülsmeier Thorsten Hornemann Jesper V. Olsen Yi Wang Roberto Gramignoli Michael Sundström Volker M. Lauschke Chemogenomic Screening in a Patient‐Derived 3D Fatty Liver Disease Model Reveals the CHRM1‐TRPM8 Axis as a Novel Module for Targeted Intervention Advanced Science chemical probes fibrosis muscarinic receptor NASH phenotypic assay target discovery |
| title | Chemogenomic Screening in a Patient‐Derived 3D Fatty Liver Disease Model Reveals the CHRM1‐TRPM8 Axis as a Novel Module for Targeted Intervention |
| title_full | Chemogenomic Screening in a Patient‐Derived 3D Fatty Liver Disease Model Reveals the CHRM1‐TRPM8 Axis as a Novel Module for Targeted Intervention |
| title_fullStr | Chemogenomic Screening in a Patient‐Derived 3D Fatty Liver Disease Model Reveals the CHRM1‐TRPM8 Axis as a Novel Module for Targeted Intervention |
| title_full_unstemmed | Chemogenomic Screening in a Patient‐Derived 3D Fatty Liver Disease Model Reveals the CHRM1‐TRPM8 Axis as a Novel Module for Targeted Intervention |
| title_short | Chemogenomic Screening in a Patient‐Derived 3D Fatty Liver Disease Model Reveals the CHRM1‐TRPM8 Axis as a Novel Module for Targeted Intervention |
| title_sort | chemogenomic screening in a patient derived 3d fatty liver disease model reveals the chrm1 trpm8 axis as a novel module for targeted intervention |
| topic | chemical probes fibrosis muscarinic receptor NASH phenotypic assay target discovery |
| url | https://doi.org/10.1002/advs.202407572 |
| work_keys_str_mv | AT soniayouhanna chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT aurinomkemas chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT shanecwright chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT yizhong chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT brittaklumpp chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT kathrinklein chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT aikaterinimotso chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT mauricemichel chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT nicoleziegler chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT mingmeishang chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT pierresabatier chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT aimokannt chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT hongdasheng chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT nuriaolivavilarnau chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT florianabuttner chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT brintonseashoreludlow chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT jonasschreiner chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT maikewindbergs chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT martincornillet chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT niklaskbjorkstrom chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT andreasjhulsmeier chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT thorstenhornemann chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT jespervolsen chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT yiwang chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT robertogramignoli chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT michaelsundstrom chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention AT volkermlauschke chemogenomicscreeninginapatientderived3dfattyliverdiseasemodelrevealsthechrm1trpm8axisasanovelmodulefortargetedintervention |