TY  - JOUR
AU  - Del Zompo, Fabio
AU  - Crouchet, Emilie
AU  - Ostyn, Tessa
AU  - Nehme, Zeina
AU  - Messé, Mélissa
AU  - Juehling, Frank
AU  - Désert, Romain
AU  - Vieira, Angelica T
AU  - Moehlin, Julien
AU  - Nakib, Diana
AU  - Andrews, Tallulah
AU  - Perciani, Catia
AU  - Chung, Sai
AU  - Bader, Gary
AU  - McGilvray, Ian
AU  - Caime, Chiara
AU  - Scaravaglio, Miki
AU  - Carbone, Marco
AU  - Invernizzi, Pietro
AU  - Yaqub, Sheraz
AU  - Folseraas, Trine
AU  - Karlsen, Tom H
AU  - Shankar, Gautam
AU  - Primeaux, Mark
AU  - Dhawan, Punita
AU  - Banales, Jesus M
AU  - Roehlen, Natascha
AU  - Iacone, Roberto
AU  - Teixeira, Geoffrey
AU  - Heikenwälder, Mathias
AU  - Mailly, Laurent
AU  - MacParland, Sonya
AU  - Roskams, Tania
AU  - Govaere, Olivier
AU  - Schuster, Catherine
AU  - Baumert, Thomas F
TI  - Claudin-1 is a mediator and therapeutic target in primary sclerosing cholangitis.
JO  - Journal of hepatology
VL  - nn
SN  - 0168-8278
CY  - Amsterdam [u.a.]
PB  - Elsevier Science
M1  - DKFZ-2025-01754
SP  - nn
PY  - 2025
N1  - epub
AB  - 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.
KW  - antibody therapy (Other)
KW  - biliary fibrosis (Other)
KW  - cholangiopathies (Other)
KW  - proof-of-concept (Other)
KW  - signaling (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:40846184
DO  - DOI:10.1016/j.jhep.2025.08.005
UR  - https://inrepo02.dkfz.de/record/304086
ER  -