Disrupting the Formation of YAP Condensates Promotes the Activation of AMPKα to Inhibit the Progression of Primary Liver Cancer

ABSTRACT Liquid‐liquid phase separation, a process facilitating biomolecular condensate formation, plays a critical role in various pathologies, including tumorigenesis, metabolic disorders, and neurodegenerative diseases. 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‐associated 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‐Myc)‐induced hepatocellular carcinoma, myristoylated AKT (myr‐AKT)‐induced intrahepatic cholangiocarcinoma, and amino‐terminal missing first 90 amino acids of catenin beta 1 ( Δ N90‐CTNNB1)‐induced hepatoblastoma. We found that the YAP phase separation inhibits the activation of the adenosine monophosphate‐activated 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)‐derived peptide effectively disrupted YAP condensate formation, leading to AMPKα 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.