Ascites circRNA ASCOR Drives Platinum Resistance of High-Grade Serous Ovarian Cancer by Facilitating RPA1 Nuclear Translocation

Abstract

High-grade serous ovarian carcinoma (HGSOC) remains the most lethal gynecologic malignancy, with platinum resistance posing the major therapeutic barrier. Malignant ascites, a hallmark of advanced HGSOC, correlates with chemoresistance and poor prognosis, yet the contribution of ascites circRNAs in this process remains obscure. Here, we identify ASCOR, a circRNA upregulated in ascites small extracellular vesicles (sEVs) from platinum-resistant HGSOC patients, predicts poor survival. ASCOR promotes platinum resistance in vitro and in vivo by enhancing cell viability, reducing apoptosis, and alleviating DNA damage, with effects also transferred via sEVs. Mechanistically, ASCOR binds RPA1 and facilitates its NUP153-dependent nuclear translocation, which recruits the RNA helicase DDX18, suppressing R-loop formation. Meanwhile, the ASCOR-RPA1-DDX18 axis activates PI3K/Akt signaling to promote platinum resistance. Targeting ASCOR with antisense oligonucleotides reverses chemoresistance in mouse models. Our study unveils an ascites circRNA-driven pathway underlying platinum resistance in HGSOC, suggesting targeting ASCOR is a promising strategy for HGSOC treatment.