%0 Journal Article
%A Del Zompo, Fabio
%A Crouchet, Emilie
%A Ostyn, Tessa
%A Nehme, Zeina
%A Messé, Mélissa
%A Juehling, Frank
%A Désert, Romain
%A Vieira, Angelica T
%A Moehlin, Julien
%A Nakib, Diana
%A Andrews, Tallulah
%A Perciani, Catia
%A Chung, Sai
%A Bader, Gary
%A McGilvray, Ian
%A Caime, Chiara
%A Scaravaglio, Miki
%A Carbone, Marco
%A Invernizzi, Pietro
%A Yaqub, Sheraz
%A Folseraas, Trine
%A Karlsen, Tom H
%A Shankar, Gautam
%A Primeaux, Mark
%A Dhawan, Punita
%A Banales, Jesus M
%A Roehlen, Natascha
%A Iacone, Roberto
%A Teixeira, Geoffrey
%A Heikenwälder, Mathias
%A Mailly, Laurent
%A MacParland, Sonya
%A Roskams, Tania
%A Govaere, Olivier
%A Schuster, Catherine
%A Baumert, Thomas F
%T Claudin-1 is a mediator and therapeutic target in primary sclerosing cholangitis.
%J Journal of hepatology
%V nn
%@ 0168-8278
%C Amsterdam [u.a.]
%I Elsevier Science
%M DKFZ-2025-01754
%P nn
%D 2025
%Z epub
%X 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.
%K antibody therapy (Other)
%K biliary fibrosis (Other)
%K cholangiopathies (Other)
%K proof-of-concept (Other)
%K signaling (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:40846184
%R 10.1016/j.jhep.2025.08.005
%U https://inrepo02.dkfz.de/record/304086