Because of having less early diagnostic biomarkers with great specificity and awareness, patients with HCC usually fail to receive timely treatment2. region Docosahexaenoic Acid methyl ester of YAP 3UTR, and this m6A modification was essential for the interaction between miR-582-3p and YAP 3UTR. Further, the diagnostic performance of circ_104075 was evaluated. The area under the receiver operating characteristic (AUC-ROC) for circ_104075 was 0.973 with a sensitivity of 96.0% and a specificity of 98.3%. Collectively, we determined that circ_104075 was highly expressed in HCC and elucidated its upstream and downstream regulatory mechanisms. circ_104075 additionally has the potential to serve as a new diagnostic biomarker in HCC. Targeting circ_104075 may provide new strategies in HCC diagnosis and therapy. Introduction Primary liver cancer is the third most common cause of cancer-related death worldwide1. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer. Because of the lack of early diagnostic biomarkers with high specificity and sensitivity, patients with HCC usually fail to receive timely treatment2. The classical biomarkers for clinical diagnosis include -fetoprotein (AFP)3, -fetoprotein-L3 (AFP-L3)4, and des-carboxy-prothrombin (DCP)5. However, these biomarkers lead to some false-positive and false-negative results in HCC diagnosis. Therefore, novel diagnostic biomarkers for HCC are still urgently needed. Since most protein-based assays lack the desired accuracy, non-coding RNA-based assays could be considered as alternative diagnostic tools for HCC6. Emerging evidences have suggested that non-coding RNAs play a diagnostic role in HCC6. Considering long non-coding RNA (lncRNA), urothelial carcinoma associated-1 (UCA1) has been reported as a biomarker for lncRNA-based HCC diagnostic approach. The reported sensitivities are higher than 90% and the specificities are higher than 82% for UCA17,8. Other lncRNA biomarkers such as HULC9, DANCR10, and linc0122511 are reported to possess good sensitivity and specificity Docosahexaenoic Acid methyl ester in HCC diagnosis. Moreover, certain types of microRNAs are aberrantly expressed in HCC, and they have the ability to distinguish HCC patients from healthy control subjects. Data from meta-analysis showed that miR-21 exhibits a sensitivity of 86.6% and a specificity of 79.5% in HCC diagnosis12. Several studies have provided evidences that miR-223 is upregulated and has the potential to become a diagnostic biomarker in HCC13C15. Compared to linear non-coding RNAs, circular RNA (circRNA) is highly stable because of its covalently closed loop structure16. Some types of circRNAs are abnormally expressed in the tissues or serum of HCC patients, and they exhibit pro-tumorigenic roles17. For instance, circRNA_10720 promotes EMT by absorbing microRNAs that target vimentin to stimulate HCC tumorigenesis both in vitro and in vivo18. Another example is circRNA_0016788, which acts as a sponge for miR-486, stimulates the expression of CDK4, and promotes tumor growth in HCC19. Because of its critical function in the development of HCC and its relatively stable characteristics, circRNA exhibits the potential to serve as a novel biomarker in HCC diagnosis. Docosahexaenoic Acid methyl ester Here, we revealed that circRNA_104075 was highly expressed in HCC cell line and tissues and serum of HCC patients, and the expression of circRNA_104075 was stimulated by HNF4a. Moreover, circRNA_104075 promoted HCC tumorigenesis by absorbing the inhibitor of YAP, miR-582-3p. N6-methyladenosine (m6A) modification of the motif in the 353C357 region of YAP 3UTR promoted YAP inhibition via miR-582-3p. Finally, the diagnostic potential of circRNA_104075 was analyzed, and we found that circRNA_104075 was able to predict the occurrence of HCC. The AUC-ROC for circ_104075 was 0.973 with a sensitivity of 96.0% and a specificity of 98.3%. Results circ_104075 was highly expressed in HCC Microarray data were collected from three studies on circRNA expression in HCC vs Healthy tissues. Ten circRNAs were identified to be highly expressed in HCC in the study performed by Huang et al.20, 258 circRNAs were identified to be highly expressed in HCC in the study performed by Fu et al.21, and 456 circRNAs were identified as highly expressed in HCC in the study performed by Han et al.22. Only circRNA_104075 (circ_104075) was found to be highly expressed in all three studies (Fig.?1a). Upon evaluating ten pairs of clinical liver tissues, a higher level of circ_104075 was detected in HCC tissues compared to adjacent normal tissues (Fig.?1b). A higher expression of circ_104075 was also observed in established HCC cell lines (Bel-7402, IKZF3 antibody Bel-7404, SMMC-7721, HepG2, Hep1, and Huh7) compared to normal hepatocyte lines (THLE-3 and HL-7702) (Fig.?1c). Moreover, we detected the level of circ_104075 and several reported lncRNA and microRNA HCC.