{"entity": "publication", "iuid": "b64aaec3f7fd4a65b9006c5e890fa871", "timestamp": "2026-09-26T11:30:12.349Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/b64aaec3f7fd4a65b9006c5e890fa871.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/b64aaec3f7fd4a65b9006c5e890fa871"}}, "title": "Chemogenomic Screening in a Patient-Derived 3D Fatty Liver Disease Model Reveals the CHRM1-TRPM8 Axis as a Novel Module for Targeted Intervention.", "authors": [{"family": "Youhanna", "given": "Sonia", "initials": "S"}, {"family": "Kemas", "given": "Aurino M", "initials": "AM"}, {"family": "Wright", "given": "Shane C", "initials": "SC"}, {"family": "Zhong", "given": "Yi", "initials": "Y"}, {"family": "Klumpp", "given": "Britta", "initials": "B"}, {"family": "Klein", "given": "Kathrin", "initials": "K"}, {"family": "Motso", "given": "Aikaterini", "initials": "A"}, {"family": "Michel", "given": "Maurice", "initials": "M"}, {"family": "Ziegler", "given": "Nicole", "initials": "N"}, {"family": "Shang", "given": "Mingmei", "initials": "M"}, {"family": "Sabatier", "given": "Pierre", "initials": "P"}, {"family": "Kannt", "given": "Aimo", "initials": "A"}, {"family": "Sheng", "given": "Hongda", "initials": "H"}, {"family": "Oliva-Vilarnau", "given": "Nuria", "initials": "N"}, {"family": "B\u00fcttner", "given": "Florian A", "initials": "FA"}, {"family": "Seashore-Ludlow", "given": "Brinton", "initials": "B"}, {"family": "Schreiner", "given": "Jonas", "initials": "J"}, {"family": "Windbergs", "given": "Maike", "initials": "M"}, {"family": "Cornillet", "given": "Martin", "initials": "M"}, {"family": "Bj\u00f6rkstr\u00f6m", "given": "Niklas K", "initials": "NK"}, {"family": "H\u00fclsmeier", "given": "Andreas J", "initials": "AJ"}, {"family": "Hornemann", "given": "Thorsten", "initials": "T"}, {"family": "Olsen", "given": "Jesper V", "initials": "JV"}, {"family": "Wang", "given": "Yi", "initials": "Y"}, {"family": "Gramignoli", "given": "Roberto", "initials": "R"}, {"family": "Sundstr\u00f6m", "given": "Michael", "initials": "M"}, {"family": "Lauschke", "given": "Volker M", "initials": "VM", "orcid": "0000-0002-1140-6204", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/82048d4da61547d08aa9d2bb3bae12dd.json"}}], "type": "journal article", "published": "2025-01-00", "journal": {"title": "Adv Sci (Weinh)", "issn": "2198-3844", "volume": "12", "issue": "3", "pages": "e2407572", "issn-l": null}, "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.", "doi": "10.1002/advs.202407572", "pmid": "39605182", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11744578"}], "notes": [], "created": "2026-09-23T09:07:33.272Z", "modified": "2026-09-23T09:07:33.336Z"}