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

Area of Science:

• Biochemistry
• Molecular Biology
• Oncology

Background:

• Ovarian cancer (OVCA) is a lethal gynecological malignancy with high recurrence rates due to chemoresistance.
• Ferroptosis is a promising therapeutic strategy to overcome OVCA resistance, but current inducers lack specificity.
• Developing targeted and effective ferroptosis inducers is crucial for improving OVCA treatment outcomes.

Purpose of the Study:

• To identify and characterize a novel tRNA-derived fragment (tRF-21) as a specific ferroptosis inducer for OVCA.
• To elucidate the molecular mechanisms by which tRF-21 suppresses OVCA growth.
• To develop an enhanced delivery system for tRF-21 to improve its therapeutic efficacy and reduce toxicity.

Main Methods:

• Identification of tRF-21 as a potential ferroptosis inducer.
• Investigation of tRF-21's mechanism of action involving the system Xc-/glutathione (GSH)/peroxidase 4 (GPX4) axis, SLC3A2 ubiquitination, and SLC7A11 mRNA destabilization.
• Engineering of a pH-responsive nanoplatform (tRF-21@EPH) for targeted delivery.

Main Results:

• tRF-21 selectively induces ferroptosis in OVCA by dual inhibition of the system Xc-/GSH/GPX4 axis.
• tRF-21 promotes SLC3A2 ubiquitination and destabilizes SLC7A11 mRNA, leading to GSH depletion, reactive oxygen species (ROS) accumulation, and ferroptotic cell death.
• The tRF-21@EPH nanoplatform demonstrated enhanced efficacy and reduced toxicity in OVCA treatment.

Conclusions:

• tRF-21 is a novel RNA-based therapeutic agent that effectively suppresses OVCA growth via ferroptosis induction.
• The dual inhibition mechanism of tRF-21 provides a targeted approach to overcome chemoresistance.
• The engineered nanoplatform enhances tRF-21 delivery, presenting a promising strategy for OVCA treatment with minimal side effects.