PXD052956-1

PXD052956 is an original dataset announced via ProteomeXchange.

Title	Chemogenomic screening in a patient-derived 3D model of metabolic dysfunction-associated steatohepatitis reveals the CHRM1-TRPM8 axis as a novel module for targeted intervention
Description	Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver disease. A multitude of compounds have been developed in recent years but, due to lack of efficacy or safety concerns, receiving market approval has been challenging and restricted. These failures emphasize the need for robust pre-clinical data that can narrow the translational gap. We here present an organotypic 3D liver model established from primary human hepatocytes (PHH) and non-parenchymal cells derived from patients with clinical diagnosis of MASH. The model closely recapitulates disease relevant endpoints, such as steatosis, inflammation, hepatocyte ballooning and fibrosis for multiple weeks in culture. Using integrative multi-omics profiling, we moreover identify the underlying molecular networks of MASH at the transcriptomic, proteomic and lipidomic level. Importantly, by combining biochemical and high content imaging-based multiplexed chemogenomic screening using selective, highly validated chemical probes, we identified multiple novel targets with anti-steatotic, anti-inflammatory and anti-fibrotic effects. Among these, activation of the muscarinic receptor 1 (CHRM1) using a positive allosteric modulator and inhibition of the transient receptor potential cation channel subfamily M member 8 (TRPM8) ion channel resulted in strong anti-fibrotic effects, which could be confirmed using orthogonal genetic assays. Strikingly, using an array of bioluminescence resonance energy transfer (BRET) sensors and small molecule interference, we identify a novel signaling axis in which CHRM1 inhibits TRPM8 via Gq/11 and phospholipase C-mediated depletion of phosphatidylinositol 4,5-bisphosphate (PIP2). Combined, this study presents the first scalable patient-derived 3D liver model for NASH in which disease-relevant endpoints are recapitulated ex vivo, identified a novel CHRM1-TRPM8 signaling module with anti-fibrotic effects and highlights the potential of organotypic culture systems as phenotypic assays for comprehensive chemogenomic drug target identification.
HostingRepository	PRIDE
AnnounceDate	2024-11-28
AnnouncementXML	Submission_2024-11-28_10:07:12.385.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Pierre Sabatier
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; acetylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-10 03:35:35	ID requested
⏵ 1	2024-11-28 10:07:12	announced

10.1002/ADVS.202407572;

submitter keyword: NASH

muscarinic receptor

phenotypic assay

target discovery

chemical probes

fibrosis.

Jesper V. Olsen
contact affiliation	Novo Nordisk Foundation Center for Protein Research, University of Copenhagen
contact email	jesper.olsen@cpr.ku.dk
lab head
Pierre Sabatier
contact affiliation	Department of Surgical Sciences, Uppsala University. Novo Nordisk Foundation Center for Protein Research, University of Copenhagen.
contact email	pierre63.sabatier@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/11/PXD052956

PRIDE project URI

• PRIDE
  1. PXD052956
     1. Label: PRIDE project
     2. Name: Chemogenomic screening in a patient-derived 3D model of metabolic dysfunction-associated steatohepatitis reveals the CHRM1-TRPM8 axis as a novel module for targeted intervention