USF1-activated hsa_circ_0076691 induces oxaliplatin resistance via facilitating FGF9 expression in miR-589-3p-dependent manners

Chemotherapeutic efficacy in colorectal cancer (CRC) is significantly hindered by the development of drug resistance. Emerging evidence indicates that circular RNAs (circRNAs) play pivotal roles in various cancer-related biological processes. Nonetheless, the specific role of circRNAs in oxaliplatin resistance in CRC remains largely unexplored. In this study, hsa_circ_0076691 (circ76691) overexpression was observed in the oxaliplatin-resistant CRC group and could predict poor prognosis. Functional analyses revealed that circ76691 attenuates oxaliplatin-induced apoptosis both <i>in vitro</i> and <i>in vivo</i>, thereby contributing to enhanced oxaliplatin resistance. Mechanistically, circ76691 transcriptionally downregulates miR-589-3p expression and acts as a molecular sponge for miR-589-3p, sequestering it from its downstream targets. Notably, fibroblast growth factor 9 (FGF9), identified as a downstream inhibitory target of miR-589-3p, is subsequently upregulated due to circ76691 activity. Furthermore, circ76691 expression is transcriptionally induced by USF1 through direct binding to its promoter region. Collectively, these findings elucidate the USF1/circ76691/miR-589-3p/FGF9 axis in inhibiting oxaliplatin-induced apoptosis, suggesting circ76691 as a potential therapeutic target to enhance the efficacy of platinum-based therapy.