肝细胞癌（HCC）是一种高度侵袭性的恶性肿瘤，预后较差。广泛的研究揭示了长非编码RNA（lncRNA）在肿瘤发展调节中的重要作用。在本研究中，采用高通量测序分析来评估三对HCC组织及其相应非癌组织中lncRNA的表达水平。通过实时定量聚合酶链反应（qRT-PCR）分析和临床病理分析，发现HNF4A-AS1在HCC组织中表达下调。此外，其表达水平被发现与HCC患者的预后呈正相关。随后的体外和体内功能研究表明，HNF4A-AS1 可抑制 HCC 细胞的增殖、侵袭和干性。从机制上看，HNF4A-AS1 通过特定片段 (491-672 nt) 与 PCBP2 的 KH3 结构域发生物理相互作用。这种相互作用促进 AIP4 招募 PCBP2，导致 PCBP2 泛素化和随后的降解。此外，HNF4A-AS1被发现可以通过调节PCBP2来调节AGR2 mRNA的稳定性，从而影响HCC的恶性表型。总体而言，我们的研究表明，HNF4A-AS1 表达的减少与临床环境中 HCC 患者的预后呈正相关。 HNF4A-AS1 可以通过促进泛素调节的 PCBP2 降解来抑制 ARG2 mRNA 的稳定性，从而抑制 HCC 进展。 HNF4A-AS1 可能作为 HCC 的潜在治疗靶点。© 作者。

Hepatocellular carcinoma (HCC) is a highly aggressive malignant tumor with a poor prognosis. Extensive research has revealed the significant role of long noncoding RNAs (lncRNAs) in the regulation of tumor development. In this study, high-throughput sequencing analysis was used to assess the expression levels of lncRNAs in three pairs of HCC tissues and their corresponding noncancerous tissues. Through quantitative real-time polymerase chain reaction (qRT-PCR) analysis and clinicopathological analysis, it was discovered that HNF4A-AS1 was downregulated in HCC tissues. Furthermore, its expression levels were found to be positively correlated with the prognosis of HCC patients. Subsequent in vitro and in vivo functional studies demonstrated that HNF4A-AS1 inhibits the proliferation, invasion, and stemness of HCC cells. Mechanistically, it was observed that HNF4A-AS1 physically interacts with the KH3 domain of PCBP2 through a specific segment (491-672 nt). This interaction facilitates the recruitment of PCBP2 by AIP4, leading to the ubiquitination and subsequent degradation of PCBP2. Furthermore, HNF4A-AS1 was found to regulate the stability of AGR2 mRNA by modulating PCBP2, thereby influencing the malignant phenotype of HCC. Overall, our study demonstrated a positive association between the decrease in HNF4A-AS1 expression and the prognosis of patients with HCC in a clinical setting. HNF4A-AS1 can suppress the stability of ARG2 mRNA by promoting the ubiquitin-modulated degradation of PCBP2, which suppresses HCC progression. HNF4A-AS1 may serve as a potential therapeutic target for HCC.© The author(s).