{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:18:11Z","timestamp":1785406691709,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,26]]},"group-title":"Pathology","reference-count":13,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,26]],"date-time":"2026-05-26T00:00:00Z","timestamp":1779753600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01DK128972 (VY)"],"award-info":[{"award-number":["R01DK128972 (VY)"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R01DK130499 (VY)"],"award-info":[{"award-number":["R01DK130499 (VY)"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,26]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background &amp; Aims<\/jats:title>\n                  <jats:p>Primary sclerosing cholangitis (PSC) is a progressive cholangiopathy characterized by ductular remodeling, inflammation, and periportal fibrosis, for which effective medical therapies remain limited. The Hippo pathway effector TEAD1 has been implicated in liver regeneration and fibrogenesis; however, its role in cholestatic injury remains poorly defined. We investigated whether hepatocyte TEAD1 regulates injury-associated remodeling in a PSC-mimicking model and whether this mechanism is conserved in human PSC liver.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Hepatocyte-specific TEAD1 knockout mice (Alb-TEAD1\n                    <jats:sup>-\/-<\/jats:sup>\n                    ) and littermate controls were subjected to DDC-induced cholestatic injury. Ductular reaction, fibrosis, inflammation, and bile acid-related gene programs were assessed by histology, immunostaining, and gene expression analyses. Translational relevance was evaluated using bulk and single-cell transcriptomic datasets from human PSC liver.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Hepatocyte TEAD1 deletion attenuated DDC-induced fibrosis, ductular expansion, and inflammatory cell accumulation, while preserving hepatocyte proliferative responses. TEAD1-deficient livers exhibited reduced expression of profibrotic mediators, including\n                    <jats:italic>Spp1, Ctgf<\/jats:italic>\n                    , and\n                    <jats:italic>Cyr61<\/jats:italic>\n                    , with decreased extracellular matrix deposition. In contrast, canonical transcriptional adaptations to cholestatic stress, including suppression of bile acid uptake, induction of efflux pathways, and repression of bile acid synthesis genes, were preserved in the absence of TEAD1.\n                  <\/jats:p>\n                  <jats:p>Analysis of human PSC datasets demonstrated coordinated upregulation of TEAD1 and TEAD-associated target genes. Single-cell transcriptomic analysis further revealed hepatocyte-enriched TEAD1 expression and activation of a TEAD1 target gene program across all hepatic zones in PSC, with effect sizes exceeding those observed in non-parenchymal populations. TEAD1 activation was accompanied by co-expression of profibrotic mediators and downregulation of hepatocyte differentiation markers, consistent with a maladaptive hepatocyte state.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Hepatocyte TEAD1 drives ductular, inflammatory, and fibrogenic remodeling during cholestatic injury without disrupting bile acid metabolic adaptation. These findings identify TEAD1 as a hepatocyte-intrinsic regulator of epithelial-stromal crosstalk and establish conserved activation of this pathway in human PSC, supporting TEAD-directed signaling as a therapeutic target.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.21.726939","type":"posted-content","created":{"date-parts":[[2026,5,30]],"date-time":"2026-05-30T03:45:23Z","timestamp":1780112723000},"source":"Crossref","is-referenced-by-count":0,"title":["Hepatocyte TEAD1 drives epithelial-stromal remodeling during cholestatic liver injury"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6650-977X","authenticated-orcid":false,"given":"Amit","family":"Kumar","sequence":"first","affiliation":[{"name":"Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0260-7397","authenticated-orcid":false,"given":"Jeongkyung","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinny","family":"Negi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Varun","family":"Mandi","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenic","family":"Filingeri","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joey","family":"Danvers","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3169-5151","authenticated-orcid":false,"given":"Rajat","family":"Pant","sequence":"additional","affiliation":[{"name":"Department of Medicine, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samit","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Medicine, Pittsburgh Heart, Lung, and Blood Vascular Medicine Institute, University of Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mousumi","family":"Moulik","sequence":"additional","affiliation":[{"name":"Division of Pediatric Cardiology, UPMC Children\u2019s Hospital of Pittsburgh, University of Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9981-6784","authenticated-orcid":false,"given":"Vijay K","family":"Yechoor","sequence":"additional","affiliation":[{"name":"Division of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026052920451764000_2026.05.21.726939v1.1","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2007.061133"},{"key":"2026052920451764000_2026.05.21.726939v1.2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI23486"},{"issue":"4","key":"2026052920451764000_2026.05.21.726939v1.3","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1016\/j.hpb.2024.12.007","article-title":"Transcription enhanced associate domain factor 1 (TEAD1) predicts liver regeneration outcome of ALPPS-treated patients","volume":"27","year":"2025","journal-title":"HPB (Oxford)"},{"issue":"4","key":"2026052920451764000_2026.05.21.726939v1.4","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1038\/s44320-024-00024-x","article-title":"Estrogen receptor activation remodels TEAD1 gene expression to alleviate hepatic steatosis","volume":"20","year":"2024","journal-title":"Mol Syst Biol"},{"issue":"5","key":"2026052920451764000_2026.05.21.726939v1.5","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1016\/j.cmet.2024.04.003","article-title":"TM7SF3 controls TEAD1 splicing to prevent MASH-induced liver fibrosis","volume":"36","year":"2024","journal-title":"Cell Metab"},{"key":"2026052920451764000_2026.05.21.726939v1.6","doi-asserted-by":"crossref","unstructured":"Mokhtari RB , Ashayeri N , Baghaie L , Sambi M , Satari K , Baluch N , Bosykh DA , Szewczuk MR , Chakraborty S. The Hippo Pathway Effectors YAP\/TAZ-TEAD Oncoproteins as Emerging Therapeutic Targets in the Tumor Microenvironment. 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