Purpose <p>Hepatocellular carcinoma (HCC), a malignancy driven by multifaceted genetic and epigenetic mechanisms, is the leading cause of cancer deaths worldwide. Long non-coding RNAs (lncRNAs), particularly super-enhancer-associated lncRNAs (SE-lncRNAs), have emerged as critical regulators of tumorigenesis. </p> Methods <p>In our study, we explored the expression of super-enhancer (SE)-associated lncRNA (seRNA) in HCC and investigated the role of a SE-lncRNA, HDAC11-AS1, in the progression of HCC. HCC-specific SE-lncRNAs were identified by H3K27ac ChIP-seq data (from ENCODE database) of Huh7, HepG2, and normal liver tissues using the ROSE algorithm. HDAC11-AS1 overexpression was validated in 36 pairs of HCC patient samples and adjacent tissues. The effects of HDAC11-AS1 on HCC proliferation and migration was analyzed in vitro and in vivo by overexpression or knockdown of HDAC11-AS1. Co-expression genes analysis of HDAC11-AS1, qPCR, western blot analysis and immunohistochemistry (IHC) were used to detect the regulation of Histone Deacetylase 11(HDAC11) and Nucleoporin 210 (NUP210).ChIA-PET data analysis, RNA pulldown and RNA immunoprecipitation (RIP) were used to explore the interaction between HDAC11-AS1 and tanscription factor (YY1)/cofactors (EP300 and SMC3). </p> Results <p>In this study, we identified HDAC11-AS1, a SE-lncRNA significantly overexpressed in HCC tissues and associated with poor prognosis. Downregulation of HDAC1-AS1 suppressed proliferation and migration of HCC in vitro and in vivo. Mechanistically, HDAC11-AS1 as a pivotal SE-lncRNA driving HCC progression through transcriptional regulation of HDAC11 and NUP210 by interacting with transcription factor YY1 and cofactor (EP300 and SMC3) in stabilizing enhancer-promoter looping. </p> Conclusions <p>Our findings reveal that HDAC11-AS1 functions as a molecular scaffold that stabilizes enhancer-promoter (E-P) looping, thereby promoting super-enhancer activity and the subsequent transcription of oncogenic drivers.</p>