Targeting circGDI2 disrupt HNRNPC-mediated mPORCN stabilization and enhance LGK-974 anti-tumor therapy in hepatocellular carcinoma

Background: The functions of circRNAs in hepatocellular carcinoma (HCC) till needs to be further elucidated. Methods: We assessed the biological functions of circGDI2 in vitro and in vivo by gain or loss of function experiments. Then, fuorescence in situ hybridization (FISH), immunofluorescence (IF), RNA pull-down, mass spectrometry, and RNA immunoprecipitation (RIP) were applied to explore the interaction between circGDI2 and heterogeneous nuclear ribonucleoprotein C (HNRNPC). Finally, in vitro and in vivo experiments were performed to explore the influence of circGDI2 on the anti-tumor activity of LGK-974, a porcupine O-acyltransferase (PORCN) inhibitor. Results: CircGDI2 was significantly overexpressed in HBV-related HCC, and its high expression was significantly associated with the growth and invasion characteristics of HCC. Functional experiments indicated that circGDI2 promoted the proliferation and metastasis of HCC cells both in vitro and in vivo. Mechanistic investigations revealed that circGDI2 physically binds to HNRNPC, facilitating its interaction with mPORCN, which stabilizes mRNA and promotes PORCN expression, thereby activating the Wnt signaling pathway and driving tumor proliferation and metastasis. Additionally, we found that the PORCN inhibitor LGK-974 effectively suppressed the proliferation and metastasis of HCC cells both in vitro and in vivo, and a series of experiments demonstrated that knocking down circGDI2 could enhance the antitumor effect of LGK-974, thereby maximizing the inhibition of HCC. Conclusion: CircGDI2 played a crucial role in the progression of HCC by interacting with HNRNPC to promote the Wnt signaling pathway. Meanwhile, LGK-974 can effectively inhibit HCC and targeting circGDI2 can enhance the antitumor effect of LGK-974. Supplementary Information: The online version contains supplementary material available at 10.1186/s12943-026-02638-1.