Epigenetic silencing of the liver‐specific lncRNA LUNAR promotes liver cancer progression via NOTCH activation

While long noncoding RNAs (lncRNAs) play critical roles in hepatocellular carcinoma (HCC) pathogenesis, the regulatory mechanisms governing liver-specific lncRNAs remain poorly defined. Here, we systematically analyzed staging-specific transcriptomic datasets to identify functionally relevant lncRNAs involved in HCC progression. We identified a liver-specific lncRNA, termed LUNAR (Liver-specific Upregulated Non-coding RNA as Down-Regulator in HCC), reflecting its high expression in normal liver tissue and its functional role in restraining tumor progression in HCC. Analyses across multiple independent patient cohorts revealed that LUNAR expression correlated with clinical outcomes in HCC. Functional assays demonstrated that restoration of LUNAR expression suppressed cell migration, invasion, and in vivo metastasis, without affecting cell proliferation. Mechanistically, LUNAR overexpression was associated with attenuation of NOTCH signaling, while its downregulation in tumors was linked to epigenetic silencing via promoter hypermethylation. Collectively, these findings identify LUNAR as a liver-enriched, epigenetically regulated lncRNA with metastasis-restraining functions. This therefore supports the potential of LUNAR as a tissue-associated biomarker and therapeutic target in HCC.