Circular SNX25 encoded radioresistance augmenter facilitates DNA damage repair in hepatocellular carcinoma by targeting BAG6-GET4 interaction.

Radiotherapy (RT) is a crucial treatment for hepatocellular carcinoma (HCC); however, resistance to radiation remains a major challenge to its effectiveness. Circular RNAs (circRNAs), traditionally considered stable non-coding RNAs, have recently gained attention for their potential to encode proteins or peptides that play crucial roles in HCC radioresistance. In this study, circSNX25 (has_circ_0004874) was identified as a novel circRNA with coding potential related to radiation resistance in HCC through circRNA sequencing, Northern blotting, and mass spectrometry (MS). We demonstrated that SNX25-215, a novel protein encoded by circSNX25, rather than the parental circSNX25 itself, promotes resistance to radiotherapy in HCC cells both in vitro and in vivo. Co-immunoprecipitation (co-IP) and molecular docking revealed that amino acids H207 and E214 of SNX25-215 are critical for binding to Golgi to ER traffic protein 4 homolog (GET4). This interaction inhibits the binding of BCL2-associated athanogene 6 (BAG6) to GET4, thereby exposing the nuclear localization sequence (NLS) of BAG6 and facilitating its nuclear translocation. This, in turn, enhances DNA damage repair, ultimately increasing resistance to ionizing radiation (IR) in HCC cells. Importantly, elevated levels of SNX25-215 lead to nuclear localization of BAG6, endowing HCC cells with radioresistant activity, which is further supported by clinical evidence. Our findings highlight the potential of circSNX25 as a prognostic biomarker and a therapeutic target for overcoming radioresistance in HCC. This study provides deeper insights into the roles that circRNA-encoded proteins play in HCC radioresistance.