Circular RNA circESYT2 serves as a microRNA‐665 sponge to promote the progression of hepatocellular carcinoma through ENO2

Circular RNAs (circRNAs) have emerged as crucial regulators in tumor progression, yet their specific role in hepatocellular carcinoma (HCC) remains largely uncharacterized. In this study, we utilized high‐transcriptome sequencing to identify the upregulation of circESYT2 (hsa_circ_002142) in HCC tissues. Functional experiments carried out in vivo and in vitro revealed that circESYT2 played a significant role in maintaining the growth and metastatic behaviors of HCC. Through integrative analysis, we identified enolase 2 (ENO2) as a potential target regulated by circESYT2 through the competitive endogenous RNA sponge mechanism. Additional gain‐ or loss‐of‐function experiments indicated that overexpression of circESYT2 led to a tumor‐promoting effect, which could be reversed by transfection of microRNA‐665 (miR‐665) mimic or ENO2 knockdown in HCC cells. Furthermore, the direct interaction between miR‐665 and circESYT2 and between miR‐665 and ENO2 was confirmed using RNA immunoprecipitation, FISH, RNA pull‐down, and dual‐luciferase reporter assays, highlighting the involvement of the circESYT2/miR‐665/ENO2 axis in promoting HCC progression. These findings shed light on the molecular characteristics of circESYT2 in HCC tissues and suggest its potential as a biomarker or therapeutic target for HCC treatment. In this study, we undertook a comprehensive investigation into the roles and molecular mechanisms of circular RNA molecule circESYT2 in hepatocellular carcinoma (HCC). The findings revealed a significant association between circESYT2 overexpression and worse prognosis in HCC patients. Mechanistically, we identified for the first time that circESYT2 overexpression facilitated HCC cell proliferation and migration both in vitro and in vivo through the sponge microRNA‐665 (miR‐665), resulting in increased expression of ENO2. Collectively, targeting the circESYT2/miR‐665/ENO2 axis could represent a novel feasible therapeutic strategy for the treatment of HCC.