Abstract

The hypoxic tumor microenvironment (TME) drives malignant progression by increasing the activity of cancer stem cells (CSCs), whose iron-dependent metabolism not only maintains their stemness but also promotes drug resistance and ferroptosis resistance by activating key signaling pathways. This study revealed that hypoxia induces circHIF1α expression in CSCs and that its expression is significantly associated with chemotherapy resistance in patients. Functional experiments confirmed that circHIF1α enhances CSC stemness by regulating iron metabolism and driving cancer progression. The mechanism involves the dual regulation of ferroptosis: binding SLC3A2 to block lysosomal degradation and sponging miR-375 to abrogate its inhibition of SLC7A11, synergistically activating system Xc⁻-mediated glutathione synthesis for ferroptosis resistance. Additionally, circHIF1α can be transferred between cells in the TME via exosomes, promoting iron metabolic reprogramming and the spread of drug resistance. Based on this mechanism, we developed a cell membrane-coated siRNA nanodelivery system targeting circHIF1α and confirmed that the combination of this system with cisplatin exerted a synergistic antitumor effect. This study demonstrated that circHIF1α maintains ferroptosis resistance and a “high-iron metabolic” state in CSCs by preserving the antioxidant barrier, providing novel insights into the mechanism of circular RNAs and potential targets/strategies for overcoming chemotherapy resistance in ovarian cancer.