A Tumor‐Targeted tRF Therapeutics Triggers Ovarian Cancer Ferroptosis via Dual Inhibition of System Xc −

ABSTRACT The severe chemoresistance‐caused high recurrence has made ovarian cancer (OVCA) the most lethal gynecological malignancy in clinical practice. Ferroptosis represents a promising therapeutic approach for OVCA, which could effectively overcome tumor resistance. Nevertheless, the traditional ferroptosis inducers lack specificity and selectivity, resulting in poor therapeutic effects. Here, we identified a novel tRNA‐derived fragment, tRF‐21‐XSXMSL73E (tRF‐21), which could serve as a ferroptosis inducer to efficiently suppress OVCA growth through dual inhibition of the system Xc − /glutathione (GSH)/peroxidase 4 (GPX4) axis without causing obvious side effects. Mechanistically, tRF‐21 promotes SLC3A2 ubiquitination via SPOP E3 ligase and destabilizes SLC7A11 mRNA by disrupting NSUN2‐mediated m 5 C methylation. This dual‐inhibition effect on the system Xc − /GSH/GPX4 axis leads to GSH depletion, reactive oxygen species (ROS) accumulation, and ferroptotic cell death. To enhance therapeutic delivery, we engineered a pH‐responsive nanoplatform (tRF‐21@EPH) with an ellagic acid core, polyetherimide (PEI) intermediate layer, and hyaluronic acid shell, enabling nuclease protection and tumor‐specific uptake. This system markedly improved tRF‐21 efficacy with minimal toxicity, providing a novel RNA‐based strategy for OVCA treatment.