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The extremely low-response rates to current systemic regimens and the emergence of adaptive resistance to targeted therapies underscore the urgent need for alternative therapeutic strategies. Given that the lineage-defining transcription factors SOX9 and YAP1 are central regulators of cholangiocyte and iCCA identity, we investigated their functional roles as potential therapeutic vulnerabilities across multiple preclinical models.Methods: Patient tissue-microarray analysis, Sleeping Beauty hydrodynamic tail vein injection\u2013based iCCA models, and Cre-mediated inducible gene deletion systems were used to investigate the roles of &lt;i&gt;Sox9&lt;\/i&gt; and &lt;i&gt;Yap1&lt;\/i&gt;. Deep-learning\u2013 based prediction, RNA-seq, chromatin immunoprecipitation sequencing and immunohistochemistry analyses were performed to delineate transcriptional networks and downstream effectors associated with SOX9\/ YAP1 signaling.Results: Dual deletion of &lt;i&gt;Sox9&lt;\/i&gt; and &lt;i&gt;Yap1&lt;\/i&gt; effectively eradicated advanced iCCA while preserving intrahepatic bile ducts, regardless of oncogenic drivers. Mechanistically, SOX9 and YAP1 transcriptionally compensated for each other when one was absent, and &lt;i&gt;ILF2&lt;\/i&gt; and &lt;i&gt;MGAT5&lt;\/i&gt; were identified as key downstream effectors mediating this compensatory mechanism. Loss of &lt;i&gt;Ilf2&lt;\/i&gt; and &lt;i&gt;Mgat5&lt;\/i&gt; suppressed iCCA, whereas overexpression of &lt;i&gt;Ilf2&lt;\/i&gt; following &lt;i&gt;Sox9&lt;\/i&gt;\/&lt;i&gt;Yap1&lt;\/i&gt; co-deletion restored tumor development, indicating that ILF2 can functionally substitute for YAP1 and SOX9 in sustaining iCCA.Conclusions: Co-targeting SOX9 and YAP1 offers a promising and safe broad-spectrum preventive\/therapeutic approach for iCCA, potentially overcoming resistance to YAP1 inhibition. The adaptive resistance mechanism identified may extend to other malignancies, providing insights for addressing the advanced resistance to YAP1-TEAD-directed therapies.<\/jats:p>","DOI":"10.3350\/cmh.2025.1170","type":"journal-article","created":{"date-parts":[[2026,4,3]],"date-time":"2026-04-03T07:20:24Z","timestamp":1775200824000},"page":"1305-1320","update-policy":"https:\/\/doi.org\/10.3350\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Co-repression of Yap1 and Sox9 abrogates established cholangiocarcinoma by eliminating transcriptional compensation"],"prefix":"10.3350","volume":"32","author":[{"given":"Minwook","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA"},{"name":"Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, University of Pittsburgh, School of Medicinec"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shikai","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA"},{"name":"Department of Clinical Medicine, School of Medicine, Tsinghua Medicine, Tsinghua University, Beijing, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoojeong","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Kwon","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Molina","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA"},{"name":"Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Ju","family":"Wang","sequence":"additional","affiliation":[{"name":"University of Pittsburgh Medical Center Hillman Cancer Center, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA"},{"name":"Organ Pathobiology and Therapeutics Institute, University of Pittsburgh, School of Medicine, Pittsburgh, PA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Liu","sequence":"additional","affiliation":[{"name":"Pittsburgh Liver Research Center, University of Pittsburgh Medical Center, University of Pittsburgh, School of 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