CircRNA‐mTOR Promotes Hepatocellular Carcinoma Progression and Lenvatinib Resistance Through the PSIP1/c‐Myc Axis

Abstract Circular RNAs (circRNAs) are crucial regulators of targeted drug resistance in hepatocellular carcinoma (HCC). However, the specific mechanisms underlying resistance that significantly hampers the effectiveness of HCC treatments remain unclear. Here, it is found that circRNA‐mTOR is highly expressed in HCC and strongly correlated with patient prognosis. Furthermore, circRNA‐mTOR enhances the stemness of HCC cells, thereby promoting the progression of HCC and contributing to lenvatinib resistance. Mechanistically, circRNA‐mTOR promotes the nuclear translocation of the RNA‐binding protein (RBP) PC4 and SRSF1 interacting protein 1 (PSIP1) through specific binding. The enhancement of HCC cell stemness by circRNA‐mTOR occurs via the PSIP1/c‐Myc signaling pathway, ultimately driving HCC progression and lenvatinib resistance. This study highlights the important role of circRNA‐mTOR in HCC progression and the maintenance of lenvatinib resistance and underscores its potential as a biomarker for the diagnosis and prognosis of HCC. In conclusion, this study provides an experimental foundation for targeted drug therapy in HCC and offers novel insights, perspectives, and methodologies for understanding the development and occurrence of this disease. These findings are significant for the development of new diagnostic and therapeutic markers for HCC, with the ultimate goal of reducing drug resistance.