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Dysregulated phase separation has been linked to tumor initiation and progression. However, the pathological significance of phase separation in primary tumors of mice remains largely unexplored. We constructed a series of primary liver cancer models via hydrodynamic tail vein injection and confirmed that endogenous Yes\u2010associated protein (YAP) formed numerous condensates in primary liver cancer of mice. Deletion, mutagenesis, and replacement assays confirmed that the formation of YAP condensates plays a critical role in the development of cellular myelocytomatosis oncogene (c\u2010Myc)\u2010induced hepatocellular carcinoma, myristoylated AKT (myr\u2010AKT)\u2010induced intrahepatic cholangiocarcinoma, and amino\u2010terminal missing first 90 amino acids of catenin beta 1 (\n                    <jats:italic>\u0394<\/jats:italic>\n                    N90\u2010CTNNB1)\u2010induced hepatoblastoma. We found that the YAP phase separation inhibits the activation of the adenosine monophosphate\u2010activated protein kinase (AMPK) signaling pathway, thereby promoting the occurrence and development of primary liver cancer. Additionally, we identified that the TEA domain transcription factor 1 (TEAD1)\u2010derived peptide effectively disrupted YAP condensate formation, leading to AMPK\u03b1 activation in vivo and inhibition of primary liver cancer progression. This study systematically confirms that YAP phase separation plays a crucial role in the progression of various primary liver cancers and further substantiates that strategic disruption of these condensates constitutes an effective treatment for primary liver cancer in vivo.\n                  <\/jats:p>","DOI":"10.1002\/advs.202512866","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T07:28:02Z","timestamp":1767598082000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Disrupting the Formation of YAP Condensates Promotes the Activation of AMPK\u03b1 to Inhibit the Progression of Primary Liver Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Shuang\u2010Zhou","family":"Peng","sequence":"first","affiliation":[{"name":"School of Pharmaceutical Sciences Fujian Provincial Key Laboratory of Innovative Drug Target Research Xiamen University  Xiamen 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