MOV10 suppresses circRNA biogenesis by disrupting reverse complementary matches structure to drive hepatocarcinogenesis.

Circular RNAs (circRNAs) are frequently downregulated in hepatocellular carcinoma (HCC), yet the molecular underpinnings of this phenomenon remain poorly understood. Although reverse complementary matches (RCMs) are essential for circRNA biogenesis, how their integrity is regulated in cancer has not been explored. Here, we conducted a systematic analysis correlating the expression of RNA helicases with global circRNA levels in HCC patient cohorts. MOV10 was identified as the top candidate, and its mechanism of regulating circRNAs was verified using various molecular biology approaches. The impact of MOV10 on the competing endogenous RNA (ceRNA) network was assessed through sequencing and molecular detection, and its effects on HCC cells were validated via cell biology assays, xenograft models, and clinical samples. Our findings reveal that the global downregulation of circRNAs in HCC is associated with overexpression of RNA helicases. Among these, MOV10 is significantly overexpressed in HCC, and its high expression correlates with poor patient survival. Mechanistically, MOV10 directly binds to RCMs and, through its helicase activity, disrupts the RNA secondary structures required for back-splicing, thereby reducing circRNA biogenesis. Consequently, MOV10 broadly downregulates a subset of RCM-containing tumor-suppressive circRNAs, including hsa_circ_0080210, hsa_circ_0008797, and hsa_circ_0000182, disrupting the ceRNA network and ultimately promoting HCC cell proliferation, migration, and tumor growth. Collectively, this study identifies MOV10 as a previously unrecognized master regulator of circRNA biogenesis that drives HCC progression through direct disruption of RCM-mediated circularization, offering a new perspective on post-transcriptional regulation in cancer and positioning MOV10 as a promising therapeutic target for HCC.