Abstract
BACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of tumour-related death with late diagnoses and high recurrences. Circular RNA (circRNA) plays crucial roles in human malignancies. However, despite the potential as therapeutic target, the role of circRNA and their regulatory network in hepatocellular carcinoma (HCC) remains unclear. METHODS: Comprehensive bioinformatics approaches were utilized to systematically identify differentially expressed circRNAs (DEcircRNAs) from multiple databases. The ceRNA regulatory network was constructed and the prognostic analysis was performed to screen out hub genes. Pan-cancer, bulk tissue RNA-sequences and single-cell sequences analysis were applied to explore the genetic characteristics and immune landscape of hub genes. By a series of functional assays, the effect of hub circRNA on HCC proliferation, migration and autophagy was assayed both in vitro and in vivo. Dual luciferase reporter and rescue assay were performed for the mechanistic study. RESULTS: A total of 36 DEcircRNAs were identified and 20 of them were predicted binding with miRNAs binding sites potentially. After establishing the ceRNA regulatory network, functional enrichment, PPI network and prognostic analysis, YWHAZ was discovered as a hub gene in HCC and the subnetwork of hsa_circ_0016662/hsa-miR-22-3p/YWHAZ was recognized. Pan-cancer analysis revealed that YWHAZ was overexpressed and correlated with poor prognosis in most cancers with a 15% frequency of genetic alterations. Multiomics analysis from bulk RNA-sequencing and single-cell RNA-sequencing showed that YWHAZ was a preferable diagnostic and prognostic biomarker in HCC. YWHAZ was associated with suppressive immune microenvironment via positively correlated with the enrichment of macrophages and Tregs, as well as the immunosuppression genes. Real-word cohort validated that hsa_circ_0016662 and YWHAZ were upregulated in HCC while hsa-miR-22-3p was downregulated. Knockdown of hsa_circ_0016662 suppressed HCC malignant progression both in vitro and in vivo. Autophagy participated in hsa_circ_0016662-regulated HCC progression via sponging with hsa-miR-22-3p. CONCLUSIONS: Our study identified hsa_circ_0016662 as a novel prognostic biomarker of HCC, promoting HCC progression by sponging with hsa-miR-22-3p via autophagy regulation. Targeting hsa_circ_0016662 might be a potential therapeutic strategy for HCC. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-06763-1.