circCCNY enhances lenvatinib sensitivity and suppresses immune evasion in hepatocellular carcinoma by serving as a scaffold for SMURF1 mediated HSP60 degradation.

Lenvatinib is the standard first-line therapy for advanced hepatocellular carcinoma (HCC), but drug resistance significantly hampers its efficacy. Increasing evidence has shown that circular RNAs (circRNAs) play critical roles in HCC pathogenesis. However, the underlying mechanisms of lenvatinib sensitivity regulated by circRNAs remain largely unclear. The present study aims to identify circRNAs involved in lenvatinib resistance, as well as to elucidate the underlying mechanisms. High-throughput sequencing revealed that hsa_circ_0000235 (circCCNY) was downregulated in matched HCC tumor tissues and lenvatinib-resistant cells. Both in vitro and in vivo experiments revealed that downregulation of circCCNY could induce lenvatinib resistance in HCC cells. Subsequently, RNA pull-down, mass spectrometry, and RNA immunoprecipitation techniques were employed to investigate the interactions between circCCNY, HSP60, and the E3 ubiquitin ligase SMURF1. Briefly, circCCNY bounds to HSP60, subsequently leading to HSP60 ubiquitination and degradation through its interaction with the E3 ubiquitin ligase SMURF1. As a result, HSP60 degradation released Raf kinase inhibitor protein (RKIP), leading to the inactivation of the MAPK signaling pathway, and subsequently enhanced the anti-tumor effect of lenvatinib against HCC. Moreover, we also demonstrated that circCCNY could enhance CD8 T-cell infiltration and suppress immune evasion through inhibiting the MAPK/c-Myc/PD-L1 signaling pathway. Our findings revealed that circCCNY enhances HCC sensitivity to lenvatinib and suppresses immune evasion by inhibiting the MAPK signaling pathway in HCC. This suggests that circCCNY could serve as a promising therapeutic target in HCC treatment and a potential biomarker for predicting HCC sensitivity to lenvatinib.