Dual inhibition of GPX4 and LCN2 via miR-214–3p loaded iron oxide nanoparticles for enhancing ferroptosis in liver cancer

Abstract

Liver cancer, particularly hepatocellular carcinoma (HCC), presents significant therapeutic challenges due to factors such as drug resistance and systemic toxicity. Ferroptosis, an iron-dependent form of cell death, offers a promising alternative to overcome these challenges. This study investigates the use of folic acid-modified iron oxide nanoparticles as a delivery system for miR-214–3p to promote ferroptosis in liver cancer cells. The folic acid modification enhances the efficiency of nanoparticle-mediated miR-214–3p delivery, thereby improving its therapeutic potential. miR-214–3p plays a dual role in promoting ferroptosis: first, by downregulating lipocalin-2 (LCN2), it acts synergistically with iron oxide nanoparticles to increase intracellular iron levels, reduce iron excretion, and promote the Fenton reaction; second, by inhibiting glutathione peroxidase 4 (GPX4), it weakens cellular antioxidant defenses, further promoting ferroptosis. Our in vitro experiments demonstrated that the folic acid-modified nanoparticles effectively delivered miR-214–3p, resulting in significant ferroptosis in liver cancer cells. Animal models showed that FeNP/miR could effectively target tumors and had excellent tumor suppressive effects. This research highlights a promising approach for targeting HCC through enhanced nanoparticle-based gene therapy, offering a potential strategy in cancer treatment.