Ferrodoxin 1 (FDX1) drives paclitaxel resistance in ovarian cancer via copper metabolism and ULK1/ATG13-mediated autophagy: overcome by pH/ROS-responsive PPD/PDP@si-FDX1 nanomicelles.

BACKGROUND

Ovarian cancer (OC) is often characterized by poor prognosis due to paclitaxel (TAX) resistance, with ferredoxin 1 (FDX1) emerging as a key mediator of copper metabolism. The present study aimed to elucidate the role of FDX1 in TAX resistance and to evaluate the efficacy of pH/reactive oxygen species (ROS)-responsive nanomicelles (PPD/PDP@si-FDX1) in reversing this resistance.

METHODS

TAX-resistant A2780 and SKOV3 cells were established by gradient exposure, and FDX1 expression was assessed using Western blotting. FDX1 was either overexpressed or silenced, and resistance was evaluated using CCK-8, clonogenic, scratch, and Transwell assays. Autophagic activity was examined through Western blotting, immunofluorescence, and transmission electron microscopy. Mechanistic validation involved the ULK1 activator BL-918 and the copper chelator TTM. PPD/PDP@si-FDX1 nanomicelles were prepared via self-assembly, with structural and responsive characteristics analyzed by transmission electron microscopy (TEM), dynamic light scattering (DLS), and drug release profiling. Tumor penetration and in vivo antitumor efficacy were examined using multicellular spheroids and subcutaneous xenograft models.

RESULTS

FDX1 overexpression elevated intracellular copper, activated the ULK1/ATG13 autophagic axis, and enhanced TAX resistance; silencing FDX1 reversed these effects. Copper chelators or ULK1 inhibition phenocopied FDX1 silencing. PPD/PDP@si-FDX1 demonstrated pH/ROS-responsive tumor accumulation and enhanced si-FDX1 delivery. In vivo, it significantly suppressed tumor growth and restored TAX sensitivity, outperforming free si-FDX1.

CONCLUSION

FDX1 drives TAX resistance via copper-dependent ULK1/ATG13 activation; PPD/PDP@si-FDX1 nanomicelles effectively reverse resistance, offering a promising strategy for OC therapy.