CircARHGAP12 suppresses cisplatin-induced alkaliptosis in nasopharyngeal carcinoma through G3BP1-mediated upregulation of CA9 in an RNA G-quadruplex-dependent manner

Background Nasopharyngeal carcinoma (NPC) is a malignant epithelial tumor with a high prevalence in Southern China, and cisplatin remains a commonly used first-line chemotherapeutic agent. However, the effectiveness of cisplatin-based therapy is often compromised by the development of drug resistance, posing a major clinical challenge. Our previous studies demonstrated that circular RNA circARHGAP12 is highly expressed in NPC and promotes tumor cell migration and invasion, although its other potential functions remain unclear. Methods To evaluate the effect of circARHGAP12 on cisplatin resistance, MTT assays, colony formation assays, and nude mouse xenograft models were utilized in vitro and in vivo. Targeted genes of circARHGAP 12 were screened by RNA sequencing, combined with RT-qPCR, western blotting, and rescue experiments to validate their functions. RNA pulldown, RNA immunoprecipitation (RIP), dual-luciferase reporter assays, and actinomycin D experiments were used to elucidate the circARHGAP12/G3BP1/CA9 regulatory axis. Analysis of stress granule dynamics using immunofluorescence, fluorescence in situ hybridization, and fluorescence recovery after photobleaching (FRAP). Results In this study, we found that circARHGAP12 confers cisplatin resistance in NPC by suppressing cisplatin-induced alkaliptosis, a process mediated by the upregulation of carbonic anhydrase 9 (CA9) and reversed upon CA9 knockdown. Mechanistically, circARHGAP12 stabilizes CA9 mRNA in an RNA G-quadruplex (rG4)-dependent manner through interaction with the RNA-binding protein G3BP1. In addition, circARHGAP12 enhances the assembly of cisplatin-induced stress granules, an effect abolished by either G3BP1 silencing or treatment with pyridostatin (PDS), which disrupts the G3BP1-rG4 interaction. Conclusions Collectively, our findings reveal a novel role of circARHGAP12 in mediating cisplatin resistance in NPC through G3BP1-dependent stabilization of CA9 mRNA and modulation of stress granule dynamics. Targeting the circARHGAP12–G3BP1–CA9 axis may therefore represent a promising therapeutic strategy to overcome chemotherapy resistance in NPC.