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| 001 | 304086 | ||
| 005 | 20250831022506.0 | ||
| 024 | 7 | _ | |a 10.1016/j.jhep.2025.08.005 |2 doi |
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| 024 | 7 | _ | |a 1600-0641 |2 ISSN |
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| 037 | _ | _ | |a DKFZ-2025-01754 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Del Zompo, Fabio |b 0 |
| 245 | _ | _ | |a Claudin-1 is a mediator and therapeutic target in primary sclerosing cholangitis. |
| 260 | _ | _ | |a Amsterdam [u.a.] |c 2025 |b Elsevier Science |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1756189374_30609 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
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| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 500 | _ | _ | |a epub |
| 520 | _ | _ | |a Primary sclerosing cholangitis (PSC) is a cholangiopathy associated with high risk of development into end-stage liver disease and hepatobiliary cancer. The pathogenesis is poorly understood, and current clinical care offers limited therapeutic options, primarily relying on liver transplantation. Claudin-1 (CLDN1), a transmembrane protein highly expressed in liver epithelial cells, plays a crucial role in cell-cell communication and signaling. Here we aimed to investigate the functional role of CLDN1 as a mediator and therapeutic target for PSC using patient cohorts combined with murine and patient-derived intervention models.CLDN1 expression patterns and cell phenotypes were analyzed in liver tissues of five PSC patient cohorts using scRNAseq, spatial transcriptomics and multi-plex proteomics. Proof-of-concept studies using CLDN1-specific monoclonal antibodies (mAbs) and genetic loss-of-function were performed in state-of-the-art mouse models for PSC and cholangiopathies. Perturbation studies in human cell-based models were applied for mechanistic studies.In liver tissues of patients with PSC, CLDN1 expression was highly up-regulated and associated with disease progression. Spatial transcriptomics and proteomics uncovered high expression of CLDN1 in diseased cholangiocytes and cholestatic periportal hepatocytes with concomitant upregulation of pro-inflammatory and profibrotic signaling pathways. Therapeutic administration of CLDN1-specific mAbs or genetic knock-out improved liver function in PSC mouse models by reducing hepatobiliary fibrosis and cholestasis. Mechanistic studies revealed that mAb treatment inhibited pro-inflammatory and pro-fibrotic signaling in cholangiocytes and hepatocytes perturbed in liver tissues of patients with PSC.Our results uncover a functional role of CLDN1 in the pathogenesis of PSC and biliary fibrosis. Completed in vivo proof-of-concept studies combined with expression analyses in PSC patients pave the way for the clinical development of CLDN1-specific mAbs to treat PSC.Primary sclerosing cholangitis (PSC) is a chronic fibrosing cholangiopathy with limited therapeutic options. Here, we identified the cell surface protein Claudin-1 as a mediator and therapeutic target for PSC. Claudin-1 expression in patients is associated with disease stage and outcome. A conditional liver epithelial-specific Claudin-1 knockout in mice resulted in reduced liver injury, fibrosis and cholestasis. Monoclonal antibodies targeting Claudin-1 inhibit fibrosis and cholestasis across state-of-the-art mouse models of PSC by inhibiting pro-inflammatory and fibrogenic signaling and the ductular reaction. The results of this preclinical study pave the way for the clinical development of Claudin-1-specific antibodies for the treatment of PSC. It is therefore of impact for physicians, scientists and drug developers in the field of biliary disease. |
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| 650 | _ | 7 | |a antibody therapy |2 Other |
| 650 | _ | 7 | |a biliary fibrosis |2 Other |
| 650 | _ | 7 | |a cholangiopathies |2 Other |
| 650 | _ | 7 | |a proof-of-concept |2 Other |
| 650 | _ | 7 | |a signaling |2 Other |
| 700 | 1 | _ | |a Crouchet, Emilie |b 1 |
| 700 | 1 | _ | |a Ostyn, Tessa |b 2 |
| 700 | 1 | _ | |a Nehme, Zeina |b 3 |
| 700 | 1 | _ | |a Messé, Mélissa |b 4 |
| 700 | 1 | _ | |a Juehling, Frank |b 5 |
| 700 | 1 | _ | |a Désert, Romain |b 6 |
| 700 | 1 | _ | |a Vieira, Angelica T |b 7 |
| 700 | 1 | _ | |a Moehlin, Julien |b 8 |
| 700 | 1 | _ | |a Nakib, Diana |b 9 |
| 700 | 1 | _ | |a Andrews, Tallulah |b 10 |
| 700 | 1 | _ | |a Perciani, Catia |b 11 |
| 700 | 1 | _ | |a Chung, Sai |b 12 |
| 700 | 1 | _ | |a Bader, Gary |b 13 |
| 700 | 1 | _ | |a McGilvray, Ian |b 14 |
| 700 | 1 | _ | |a Caime, Chiara |b 15 |
| 700 | 1 | _ | |a Scaravaglio, Miki |b 16 |
| 700 | 1 | _ | |a Carbone, Marco |b 17 |
| 700 | 1 | _ | |a Invernizzi, Pietro |b 18 |
| 700 | 1 | _ | |a Yaqub, Sheraz |b 19 |
| 700 | 1 | _ | |a Folseraas, Trine |b 20 |
| 700 | 1 | _ | |a Karlsen, Tom H |b 21 |
| 700 | 1 | _ | |a Shankar, Gautam |b 22 |
| 700 | 1 | _ | |a Primeaux, Mark |b 23 |
| 700 | 1 | _ | |a Dhawan, Punita |b 24 |
| 700 | 1 | _ | |a Banales, Jesus M |b 25 |
| 700 | 1 | _ | |a Roehlen, Natascha |b 26 |
| 700 | 1 | _ | |a Iacone, Roberto |b 27 |
| 700 | 1 | _ | |a Teixeira, Geoffrey |b 28 |
| 700 | 1 | _ | |a Heikenwälder, Mathias |0 P:(DE-He78)66ed2d4ec9bc11d29b87ac006adf85e5 |b 29 |u dkfz |
| 700 | 1 | _ | |a Mailly, Laurent |b 30 |
| 700 | 1 | _ | |a MacParland, Sonya |b 31 |
| 700 | 1 | _ | |a Roskams, Tania |b 32 |
| 700 | 1 | _ | |a Govaere, Olivier |b 33 |
| 700 | 1 | _ | |a Schuster, Catherine |b 34 |
| 700 | 1 | _ | |a Baumert, Thomas F |b 35 |
| 773 | _ | _ | |a 10.1016/j.jhep.2025.08.005 |g p. S0168827825024407 |0 PERI:(DE-600)2027112-8 |p nn |t Journal of hepatology |v nn |y 2025 |x 0168-8278 |
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