Vascular invasion is a major route for intrahepatic and distant metastasis in hepatocellular carcinoma (HCC) and is a strong negative prognostic factor. Circular RNAs (circRNAs) play important roles in tumorigenesis and metastasis. However, the regulatory functions and underlying mechanisms of circRNAs in the development of vascular invasion in HCC are largely unknown.High throughput sequencing was used to screen dysregulated circRNAs in portal vein tumor thrombosis (PVTT) tissues. The biological functions of candidate circRNAs in the migration, vascular invasion, and metastasis of HCC cells were examined in vitro and in vivo. To explore the underlying mechanisms, RNA sequencing, MS2-tagged RNA affinity purification, mass spectrometry, and RNA immunoprecipitation assays were performed.circRNA sequencing followed by quantitative real-time PCR (qRT-PCR) revealed that circRNA pleckstrin and Sect. 7 domain containing 3 (circPSD3) was significantly downregulated in PVTT tissues. Decreased circPSD3 expression in HCC tissues was associated with unfavourable characteristics and predicted poor prognosis in HCC. TAR DNA-binding protein 43 (TDP43) inhibited the biogenesis of circPSD3 by interacting with the downstream intron of pre-PSD3. circPSD3 inhibited the intrahepatic vascular invasion and metastasis of HCC cells in vitro and in vivo. Serpin family B member 2 (SERPINB2), an endogenous bona fide inhibitor of the urokinase-type plasminogen activator (uPA) system, is the downstream target of circPSD3. Mechanistically, circPSD3 interacts with histone deacetylase 1 (HDAC1) to sequester it in the cytoplasm, attenuating the inhibitory effect of HDAC1 on the transcription of SERPINB2. In vitro and in vivo studies demonstrated that circPSD3 is a promising inhibitor of the uPA system.circPSD3 is an essential regulator of vascular invasion and metastasis in HCC and may serve as a prognostic biomarker and therapeutic target.© 2023. The Author(s).