{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:44:25Z","timestamp":1785422665895,"version":"3.56.0"},"posted":{"date-parts":[[2026,5,22]]},"group-title":"Physiology","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T00:00:00Z","timestamp":1779408000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["Young Investigator Award"],"award-info":[{"award-number":["Young Investigator Award"]}],"id":[{"id":"https:\/\/ror.org\/04jgqt260","id-type":"ROR","asserted-by":"publisher"}]},{"award":["K08DK140618"],"award-info":[{"award-number":["K08DK140618"]}],"id":[{"id":"https:\/\/ror.org\/001d55x84","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Introduction<\/jats:title>\n                  <jats:p>Biliary fibrosis and inflammation are central to the pathogenesis of cholangiopathies such as primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC). Inflammatory and fibrogenic stimuli, such as transforming growth factor-\u03b2 (TGF\u03b2) and lipopolysaccharide (LPS) signaling, drive these processes, but their underlying transcriptional mechanisms in cholangiocytes remain incompletely defined. We investigated the role of Runt-related transcription factor 1 (RUNX1) as a transcriptional co-regulator of fibroinflammatory signaling in cholangiocytes.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Human PSC-derived cholangiocytes (PSC-Cs) and mouse large biliary epithelial cells (MLEs) were subjected to RUNX1 knockdown or pharmacologic inhibition (Ro5-3335 or AI-10-104). Cytokine secretion was profiled by Luminex multiplexing; RUNX1 genomic binding and protein interactome were assessed by ChIP-qPCR, ChIP-seq, and LC-MS\/MS.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , Mdr2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice received Ro5-3335, and cholangiocyte-selective Runx1 knockout mice (Krt19-CreERT) were challenged with a DDC diet, followed by evaluation of fibrosis and inflammation.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    RUNX1 expression was significantly increased in cholangiocytes from PSC and PBC patients, and Mdr2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. RUNX1 knockdown or inhibition reduced IL6, TNF\u03b1, and other proinflammatory cytokines in PSC-Cs and attenuated TGF\u03b2-, LPS-, and TNF\u03b1-induced Il6 and Ccl2 expression in MLEs. ChIP-qPCR and ChIP-seq revealed TGF\u03b2-induced RUNX1 binding to the\n                    <jats:italic>Il6<\/jats:italic>\n                    promoter and 727 additional genomic sites enriched for fibrosis and inflammatory pathways; predicted upstream regulators included TGF\u03b2, TNF, and NF\u03baB signaling. Proteomic analysis identified TGF\u03b2-induced RUNX1 interactions with SMAD2 and NF\u03baB2.\n                    <jats:italic>In vivo<\/jats:italic>\n                    , Ro5-3335 treatment in Mdr2\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice reduced hepatic collagen, ECM gene expression, immune cell infiltration, and serum liver injury markers and bile acids. Similarly, cholangiocyte-specific\n                    <jats:italic>Runx1<\/jats:italic>\n                    deletion mitigated fibrosis, inflammation, and liver injury in DDC-fed mice.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>RUNX1 is a central transcriptional hub integrating TGF\u03b2 and inflammatory signals in cholangiocytes. Its inhibition attenuates biliary fibrosis and inflammation in cholestatic models, supporting RUNX1 as a potential therapeutic target in fibroinflammatory cholangiopathies.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.05.20.726667","type":"posted-content","created":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T06:30:29Z","timestamp":1779517829000},"source":"Crossref","is-referenced-by-count":0,"title":["Cholangiocyte RUNX1 Orchestrates Fibrogenic and Inflammatory Signaling to Drive Biliary Fibrosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3234-1769","authenticated-orcid":false,"given":"Sayed Obaidullah","family":"Aseem","sequence":"first","affiliation":[{"name":"Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, Virginia Commonwealth University"},{"name":"Division of Gastroenterology, Hepatology and Nutrition; Department of Internal Medicine; Virginia Commonwealth University"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Stravitz-Sanyal Institute for Liver Disease & Metabolic Health, Virginia Commonwealth University"},{"name":"Division of Gastroenterology, Hepatology and Nutrition; 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