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@ARTICLE{DelZompo:304086,
      author       = {F. Del Zompo and E. Crouchet and T. Ostyn and Z. Nehme and
                      M. Messé and F. Juehling and R. Désert and A. T. Vieira
                      and J. Moehlin and D. Nakib and T. Andrews and C. Perciani
                      and S. Chung and G. Bader and I. McGilvray and C. Caime and
                      M. Scaravaglio and M. Carbone and P. Invernizzi and S. Yaqub
                      and T. Folseraas and T. H. Karlsen and G. Shankar and M.
                      Primeaux and P. Dhawan and J. M. Banales and N. Roehlen and
                      R. Iacone and G. Teixeira and M. Heikenwälder$^*$ and L.
                      Mailly and S. MacParland and T. Roskams and O. Govaere and
                      C. Schuster and T. F. Baumert},
      title        = {{C}laudin-1 is a mediator and therapeutic target in primary
                      sclerosing cholangitis.},
      journal      = {Journal of hepatology},
      volume       = {nn},
      issn         = {0168-8278},
      address      = {Amsterdam [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DKFZ-2025-01754},
      pages        = {nn},
      year         = {2025},
      note         = {epub},
      abstract     = {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.},
      keywords     = {antibody therapy (Other) / biliary fibrosis (Other) /
                      cholangiopathies (Other) / proof-of-concept (Other) /
                      signaling (Other)},
      cin          = {D440},
      ddc          = {610},
      cid          = {I:(DE-He78)D440-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40846184},
      doi          = {10.1016/j.jhep.2025.08.005},
      url          = {https://inrepo02.dkfz.de/record/304086},
}